1-phenyl-substituted heterocyclyl derivatives and their use as prostaglandin d2 receptor modulators

ABSTRACT

The present invention relates to 1-phenyl-substituted heterocyclyl derivatives of the formula (I), 
     
       
         
         
             
             
         
       
     
     wherein Y, Z, R 1 , R 2 , R 3  and R 4  are as described in the description and their use as prostaglandin receptor modulators, most particularly as prostaglandin D 2  receptor modulators, in the treatment of various prostaglandin-mediated diseases and disorders, to pharmaceutical compositions containing these compounds and to processes for their preparation.

FIELD OF THE INVENTION

The present invention relates to 1-phenyl-substituted heterocyclylderivatives of formula (I) and their use as prostaglandin receptormodulators, most particularly as prostaglandin D₂ receptor (“DPreceptor”) modulators, in the treatment of variousprostaglandin-mediated diseases and disorders, to pharmaceuticalcompositions containing these compounds and to processes for theirpreparation. In particular, such derivatives may be used alone or inpharmaceutical compositions for the treatment of both, chronic and acuteallergic/immune diseases/disorders such as asthma, allergic asthma,eosinophilic asthma, severe asthma, rhinitis, allergic rhinitis,angioedema, insect venom allergy, drug allergies, allergic sinusitis,allergic nephritis, allergic conjunctivitis, atopic dermatitis,bronchial asthma, food allergy, systemic mast cell disorders,anaphylactic shock, urticaria, eczema, ulcerative colitis, chronicobstructive pulmonary disease (COPD), inflammatory bowel disease andrheumatoid arthritis; eosinophil-related diseases comprising smallvessel vasculitides like Churg-Strauss syndrome, Wegener'sgranulomatosis, microscopic polyangiitis (and organ-specific subsets ofthe latter), hypereosinophilic syndromes like eosinophilic pneumonia,eosinophilic esophagitis, reflux esophagitis, eosinophilic endocarditis(Loeffler's endocarditis), eosinophilia-myalgia syndrome, eosinophilicfasciitis, eosinohilic pustular folliculitis (Ofuji's disease),eosinophilic ulcers, angiolymphoid hyperplasia with eosinophilia (ALHE),eosinophilic cellulitis (Wells syndrome), chronic eosinophilic leukemiaand DRESS syndrome (Drug Rash with Eosinophilia and Systemic Symptoms);and basophil-related diseases, comprising basophilic leukemia andbasophilic leukocytosis.

BACKGROUND OF THE INVENTION

As a response to allergen exposure in allergic conditions, mast cellsare activated and release mediators like histamine, thromboxane A2(TxA2), cysteinyl leukotrienes (CysLTs) and prostaglandin D₂ (PGD₂).These mediators interact with their respective receptors and causephysiological effects such as increased vascular permeability, edema,pruritus, nasal and pulmonary congestion, bronchoconstriction, and mucussecretion. An increased vascular permeability for example, allowsexcessive infiltration of eosinophilic and basophilic leukocytes intothe tissue and thus amplifies the allergic response. Current treatmentsof allergic diseases comprise agents that can block or otherwiseinterrupt such interactions, e.g. anti-histamines (histamine H1 receptorantagonists), leukotriene receptor antagonists, beta-adrenergic receptoragonists, and corticosteroids. Generally, treatments withanti-histamines and leukotriene antagonists are limited in efficacy, andlong-term usage of corticosteroids is often associated with unwantedside effects.

PGD₂ is an agonist known to act on two G-protein-coupled receptors, thePGD₂ receptor DP1 and the recently identified CRTH2 (chemoattractantreceptor-homologous molecule expressed on Th2 cells) receptor (alsoreferred to as “DP2 receptor”).

Elevated PGD₂ levels are considered to cause inflammation as observed inallergic diseases such as allergic rhinitis, allergic asthma, allergicconjunctivitis, atopic dermatitis and the like. Therefore, blocking theinteraction of PGD₂ with its receptors is considered a usefultherapeutic strategy for the treatment of such diseases.

GB 2388540 discloses the use of ramatroban((3R)-3-(4-fluorobenzene-sulfonamido)-1,2,3,4-tetrahydrocarbazole-9-propionicacid), a TxA2 receptor (also referred to as “TP receptor”) antagonistwith additional antagonistic activity on CRTH2, for the prophylaxis andtreatment of allergic diseases, such as asthma, allergic rhinitis orallergic conjunctivitis. In T. Ishizuka et al., Cardiovascular Drug Rev.2004, 22(2), 71-90 effects of ramatroban on late-phase inflammation aredescribed. Furthermore, oral bioavailability of ramatroban and itsability to inhibit prostaglandin D₂-induced eosinophil migration invitro has been reported (Journal of Pharmacology and ExperimentalTherapeutics, 305(1), p. 347-352 (2003)).

WO 03/097598 and WO 03/097042 disclose Ramatroban analogues with CRTH2antagonistic activity. Ulven et al, J. Med. Chem. 2005, 48(4), 897-900disclose further ramatroban analogues.

CRTH2 antagonists containing a phenoxy-acetic acid moiety have been forinstance described in WO 04/089885, WO 05/105727, WO 06/056752, WO07/037187 and WO 07/052023. 1-Phenyl-1,2,3,4-tetrahydroisoquinolinederivatives have been disclosed in WO 2012/004722.

DESCRIPTION OF THE INVENTION

1) The present invention relates to 1-phenyl-substituted heterocyclylderivatives of the formula (I),

whereinY represents —NH—, —O— or a bond;Z represents O or S;R¹ represents

-   -   (C₃-C₆)alkyl which is unsubstituted, mono-substituted with        (C₁-C₄)alkoxy, or mono-, di- or tri-substituted with fluoro;    -   (C₁-C₄)alkyl which is mono-substituted with (C₄-C₆)cycloalkyl,        optionally substituted cyclopropyl, optionally substituted aryl,        optionally substituted heteroaryl, optionally substituted        heterocyclyl, optionally substituted aryloxy, optionally        substituted heteroaryloxy, or optionally substituted        aryl-(C₁-C₂)alkoxy;    -   (C₂-C₄)alkenyl which is mono-substituted with optionally        substituted aryl; or    -   (C₃-C₆)cycloalkyl which is unsubstituted, mono-substituted with        optionally substituted aryl or mono- or di-substituted with        (C₁-C₄)alkyl;        R² represents halogen or cyano;        R³ represents hydrogen or methyl;        R⁴ represents hydrogen, (C₁-C₄)alkyl, (C₃-C₆)cycloalkyl,        halogen, phenyl, (C₁-C₂)fluoroalkyl, or —NR⁵R⁶;        R⁵ represents hydrogen or methyl; and        R⁶ represents hydrogen, (C₁-C₄)alkyl, (C₁-C₄)alkyl-carbonyl,        (C₁-C₄)alkyl-sulfonyl, (C₃-C₆)cycloalkyl-carbonyl, or        (C₃-C₆)cycloalkyl-sulfonyl;        and to the salts (in particular pharmaceutically acceptable        salts) of such compounds.

The compounds of formula (I) according to embodiment 1) may contain oneor more stereogenic or asymmetric centers, such as one or moreasymmetric carbon atoms. Substituents at a double bond may be present inthe (Z)- or (E)-configuration unless indicated otherwise. The compoundsof formula (I) may thus be present as mixtures of stereoisomers orpreferably as pure stereoisomers. Mixtures of stereoisomers may beseparated in a manner known to a person skilled in the art.

Definitions provided herein are intended to apply uniformly to thecompounds of formulae (I), (I_(St1)) and (I_(St2)), as defined in anyone of embodiments 1) to 32), and, mutatis mutandis, throughout thedescription and the claims unless an otherwise expressly set outdefinition provides a broader or narrower definition. It is wellunderstood that a definition or preferred definition of a term definesand may replace the respective term independently of (and in combinationwith) any definition or preferred definition of any or all other termsas defined herein.

The term “alkyl”, used alone or in combination, refers to a straight orbranched chain alkyl group containing one to six carbon atoms. The term“(C_(x)-C_(y))alkyl” (x and y each being an integer), refers to an alkylgroup as defined before containing x to y carbon atoms. For example a(C₁-C₄)alkyl group contains from one to four carbon atoms.Representative examples of (C₁-C₄)alkyl groups include methyl, ethyl,n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl and tert-butyl.Representative examples of (C₃-C₆)alkyl groups include n-propyl,iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, pent-1-yl,pent-2-yl, pent-3-yl, 2-methyl-but-1-yl, 3-methyl-but-1-yl,2-methyl-but-2-yl, 3-methyl-but-2-yl, 2,2-dimethyl-prop-1-yl and theisomeric hexyls (notably 2,2-dimethyl-but-1-yl and3,3-dimethyl-but-1-yl). The alkyl group may be unsubstituted orsubstituted as explicitly defined.

In case “R¹” represents “(C₃-C₆)alkyl” the term means (C₃-C₆)alkylgroups as defined above. Examples of said groups are n-propyl,iso-propyl, n-butyl, iso-butyl, sec-butyl, red-butyl, pent-1-yl,pent-2-yl, pent-3-yl, 2-methyl-but-1-yl, 3-methyl-but-1-yl,2-methyl-but-2-yl, 3-methyl-but-2-yl, 2,2-dimethyl-prop-1-yl and theisomeric hexyls (notably 2,2-dimethyl-but-1-yl and3,3-dimethyl-but-1-yl). Preferred are n-propyl, n-butyl, iso-butyl,2-methyl-but-1-yl, 3-methyl-but-1-yl, 2,2-dimethyl-prop-1-yl,2,2-dimethyl-but-1-yl and 3,3-dimethyl-but-1-yl, more preferred aren-propyl, 2-methyl-but-1-yl, 3-methyl-but-1-yl, 2,2-dimethyl-but-1-yland 3,3-dimethyl-but-1-yl, and most preferred are 3-methyl-but-1-yl,2,2-dimethyl-but-1-yl and 3,3-dimethyl-but-1-yl. The alkyl group may beunsubstituted or substituted as explicitly defined. Preferred examplesof substituted (C₃-C₆)alkyl groups are 3-fluoro-prop-1-yl and 3-methoxy-3-methyl-but-1-yl.

In case “R¹” represents “(C₁-C₄)alkyl which is mono-substituted with(C₄-C₆)cycloalkyl, optionally substituted cyclopropyl, optionallysubstituted aryl, optionally substituted heteroaryl, optionallysubstituted heterocyclyl, optionally substituted aryloxy, optionallysubstituted heteroaryloxy, or optionally substituted aryl-(C₁-C₂)alkoxy”the term “(C₁-C₄)alkyl” means (C₁-C₄)alkyl groups as defined above.Examples of said groups are methyl, ethyl, n-propyl, iso-propyl,n-butyl, iso-butyl, sec-butyl and tert-butyl. Preferred are methyl,ethyl and n-propyl; most preferred are methyl and ethyl. The(C₁-C₄)alkyl groups are substituted as explicitly defined.

In case “R¹” represents “(C₃-C₆)cycloalkyl which is mono- ordi-substituted with (C₁-C₄)alkyl” the term “(C₁-C₄)alkyl” means(C₁-C₄)alkyl groups as defined above. Examples of said groups aremethyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl andtert-butyl. Preferred are methyl and ethyl and most preferred is methyl.

In case “R⁴” represents “(C₁-C₄)alkyl” the term means (C₁-C₄)alkylgroups as defined above. Examples of said groups are methyl, ethyl,n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl and tert-butyl.Preferred are methyl, ethyl, n-propyl and iso-propyl and most preferredis methyl.

In case “R⁶” represents “(C₁-C₄)alkyl” the term means (C₁-C₄)alkylgroups as defined above. Examples of said groups are methyl, ethyl,n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl and tert-butyl.Preferred is methyl.

In case “(C₁-C₄)alkyl” is a substituent to an aryl, a heteroaryl, aheterocyclyl, an aryloxy, a heteroaryloxy, or an aryl-(C₁-C₂)alkoxygroup, the term “(C₁-C₄)alkyl” means (C₁-C₄)alkyl groups as definedabove. Examples of said groups are methyl, ethyl, n-propyl, iso-propyl,n-butyl, iso-butyl, sec-butyl and tert-butyl. Preferred are methyl andethyl; most preferred is methyl.

The term “alkyl-carbonyl”, used alone or in combination, refers to analkyl-C(O)— group wherein the alkyl group is as defined before, which isattached to the rest of the molecule via the carbonyl-C-atom. The term“(C_(x)-C_(y))alkyl-carbonyl” (x and y each being an integer) refers toan alkyl-carbonyl group as defined before containing in the alkylradical x to y carbon atoms. For example a (C₁-C₄)alkyl-carbonyl groupcontains in the alkyl radical from one to four carbon atoms.Representative examples of alkyl-carbonyl groups includemethyl-carbonyl, ethyl-carbonyl, n-propyl-carbonyl, iso-propyl-carbonyl,n-butyl-carbonyl, iso-butyl-carbonyl, sec-butyl-carbonyl andtert-butyl-carbonyl.

In case “R⁶” represents “(C₁-C₄)alkyl-carbonyl” the term means(C₁-C₄)alkyl-carbonyl groups as defined above. Examples of said groupsare methyl-carbonyl, ethyl-carbonyl, n-propyl-carbonyl,iso-propyl-carbonyl, n-butyl-carbonyl, iso-butyl-carbonyl,sec-butyl-carbonyl and tert-butyl-carbonyl. Preferred aremethyl-carbonyl and ethyl-carbonyl; most preferred is methyl-carbonyl.

The term “alkyl-sulfonyl”, used alone or in combination, refers to analkyl-S(O)₂— group wherein the alkyl group is as defined before, whichis attached to the rest of the molecule via the sulfur-atom. The term“(C_(x)-C_(y))alkyl-sulfonyl” (x and y each being an integer) refers toan alkyl-sulfonyl group as defined before containing x to y carbonatoms. For example a (C₁-C₄)alkyl-sulfonyl group contains from one tofour carbon atoms. Representative examples of alkyl-sulfonyl groupsinclude methyl-sulfonyl, ethyl-sulfonyl, n-propyl-sulfonyl,iso-propyl-sulfonyl, n-butyl-sulfonyl, iso-butyl-sulfonyl,sec-butyl-sulfonyl and tert-butyl-sulfonyl.

In case “R⁶” represents “(C₁-C₄)alkyl-sulfonyl” the term means(C₁-C₄)alkyl-sulfonyl groups as defined above. Examples of said groupsare methyl-sulfonyl, ethyl-sulfonyl, n-propyl-sulfonyl,iso-propyl-sulfonyl, n-butyl-sulfonyl, iso-butyl-sulfonyl,sec-butyl-sulfonyl and tert-butyl-sulfonyl. Preferred aremethyl-sulfonyl and ethyl-sulfonyl; most preferred is methyl-sulfonyl.

The term “alkenyl”, used alone or in combination, refers to a straightor branched chain alkenyl group containing two to four carbon atoms. Theterm “(C_(x)-C_(y))alkenyl” (x and y each being an integer), refers toan alkenyl group as defined before containing x to y carbon atoms. Forexample a (C₂-C₄)alkenyl group contains from two to four carbon atoms.Representative examples of (C₂-C₄)alkenyl groups include ethenyl,propenyl, 2-methyl-propenyl and butenyl. Preferred is ethenyl. The(C₂-C₄)alkenyl group is substituted as explicitly defined.

The term “alkoxy”, used alone or in combination, refers to an alkyl-O—group wherein the alkyl group is as defined before. The term“(C_(x)-C_(y))alkoxy” (x and y each being an integer) refers to analkoxy group as defined before containing x to y carbon atoms. Forexample a (C₁-C₄)alkoxy group contains from one to four carbon atoms.Representative examples of alkoxy groups include methoxy, ethoxy,n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy andtert-butoxy.

In case “R¹” represents “(C₃-C₆)alkyl which is mono-substituted with(C₁-C₄)alkoxy” the term “(C₁-C₄)alkoxy” means (C₁-C₄)alkoxy groups asdefined above. Examples of said groups are methoxy, ethoxy, n-propoxy,iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy and tert-butoxy. Preferredis methoxy.

In case “(C₁-C₄)alkoxy” is a substituent to an aryl, a heteroaryl, aheterocyclyl, an aryloxy, a heteroaryloxy, or an aryl-(C₁-C₂)alkoxygroup, the term “(C₁-C₄)alkoxy” means (C₁-C₄)alkoxy groups as definedabove. Examples of said groups are methoxy, ethoxy, n-propoxy,iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy and tert-butoxy. Preferredis methoxy.

The term “aryl-(C₁-C₂)alkoxy” refers to an (C₁-C₂)alkoxy group asdefined above in which one hydrogen atom has been replaced with an arylgroup as defined below. Examples of aryl-(C₁-C₂)alkoxy groups arearyl-methoxy, 1-aryl-ethoxy and 2-aryl-ethoxy. Preferred isaryl-methoxy.

The term “optionally substituted cyclopropyl”, used alone or incombination, refers to a cyclopropyl group which is unsubstituted(preferred) or mono-substituted with phenyl.

The term “cycloalkyl”, used alone or in combination, refers to acycloalkyl group containing three to six carbon atoms. The term“(C_(x)-C_(y))cycloalkyl” (x and y each being an integer), refers to acycloalkyl group as defined before containing x to y carbon atoms. Forexample a (C₃-C₆)cycloalkyl group contains from three to six carbonatoms. A cycloalkyl group containing five or six carbon atoms mayoptionally be annelated to a benzene ring. Examples of (C₃-C₆)cycloalkylgroups are cyclopropyl, cyclobutyl, cyclopentyl, indanyl, cyclohexyl and1,2,3,4-tetrahydronaphthyl. The cycloalkyl group may be unsubstituted orsubstituted as explicitly defined.

In case “R¹” represents “(C₁-C₄)alkyl which is mono-substituted with(C₄-C₆)cycloalkyl” the term “(C₄-C₆)cycloalkyl” means (C₄-C₆)cycloalkylgroups as defined above. Examples of said groups are cyclobutyl,cyclopentyl, indanyl, cyclohexyl and 1,2,3,4-tetrahydronaphthyl.Preferred are cyclobutyl, indanyl and cyclohexyl; most preferred areindanyl (especially indan-2-yl) and cyclohexyl.

In case “R¹” represents “(C₃-C₆)cycloalkyl” the term means(C₃-C₆)cycloalkyl groups as defined above. Examples of said groups arecyclopropyl, cyclobutyl, cyclopentyl, indanyl, cyclohexyl and1,2,3,4-tetrahydronaphthyl. Preferred are cyclopropyl and indanyl; mostpreferred is cyclopropyl. The (C₃-C₆)cycloalkyl groups are unsubstitutedor substituted as explicitly defined.

In case “R⁴” represents “(C₃-C₆)cycloalkyl” the term means(C₃-C₆)cycloalkyl groups as defined above. Examples of said groups arecyclopropyl, cyclobutyl, cyclopentyl, indanyl, cyclohexyl and1,2,3,4-tetrahydronaphthyl. Preferred is cyclopropyl.

The term “cycloalkyl-carbonyl”, used alone or in combination, refers toa cycloalkyl-C(O)— group wherein the cycloalkyl group is as definedbefore, which is attached to the rest of the molecule via thecarbonyl-C-atom. The term “(C_(x)-C_(y))cycloalkyl-carbonyl” (x and yeach being an integer) refers to a cycloalkyl-carbonyl group as definedbefore containing in the cycloalkyl radical x to y carbon atoms. Forexample a (C₃-C₆)cycloalkyl-carbonyl group contains in the cycloalkylradical from three to six carbon atoms. Representative examples ofcycloalkyl-carbonyl groups include cyclopropyl-carbonyl,cyclobutyl-carbonyl, cyclopentyl-carbonyl and cyclohexyl-carbonyl.

In case “R⁶” represents “(C₃-C₆)cycloalkyl-carbonyl” the term means(C₃-C₆)cycloalkyl-carbonyl groups as defined above. Examples of saidgroups are cyclopropyl-carbonyl, cyclobutyl-carbonyl,cyclopentyl-carbonyl and cyclohexyl-carbonyl. Preferred iscyclopropyl-carbonyl.

The term “cycloalkyl-sulfonyl”, used alone or in combination, refers toa cycloalkyl-S(O)₂-group wherein the cycloalkyl group is as definedbefore, which is attached to the rest of the molecule via thesulfur-atom. The term “(C_(x)-C_(y))cycloalkyl-sulfonyl” (x and y eachbeing an integer) refers to a cycloalkyl-sulfonyl group as definedbefore containing x to y carbon atoms. For example a(C₃-C₆)cycloalkyl-sulfonyl group contains from three to six carbonatoms. Representative examples of cycloalkyl-sulfonyl groups includecyclopropyl-sulfonyl, cyclobutyl-sulfonyl, cyclopentyl-sulfonyl andcyclohexyl-sulfonyl.

In case “R⁶” represents “(C₃-C₆)cycloalkyl-sulfonyl” the term means(C₃-C₆)cycloalkyl-sulfonyl groups as defined above. Examples of saidgroups are cyclopropyl-sulfonyl, cyclobutyl-sulfonyl,cyclopentyl-sulfonyl and cyclohexyl-sulfonyl. Preferred iscyclopropyl-sulfonyl.

The term “(C_(x)-C_(y))fluoroalkyl” (x and y each being an integer)refers to an alkyl group as defined before containing x to y carbonatoms in which one or more (and possibly all) hydrogen atoms have beenreplaced with fluoro. For example a (C₁-C₂)fluoroalkyl group containsone or two carbon atoms in which one to five hydrogen atoms have beenreplaced with fluoro.

In case “R⁴” represents “(C₁-C₂)fluoroalkyl” the term means a(C₁-C₂)fluoroalkyl group as defined above. Examples of said groups aredifluoromethyl, trifluoromethyl, 2,2-difluoroethyl and2,2,2-trifluoroethyl. Preferred is trifluoromethyl.

In case “(C₁-C₂)fluoroalkyl” is a substituent to an aryl, a heteroaryl,a heterocyclyl, an aryloxy, a heteroaryloxy, or an aryl-(C₁-C₂)alkoxygroup, the term “(C₁-C₂)fluoroalkyl” means (C₁-C₂)fluoroalkyl groups asdefined above. Examples of said groups are difluoromethyl,trifluoromethyl, 2,2-difluoroethyl and 2,2,2-trifluoroethyl. Preferredis trifluoromethyl.

The term halogen means fluoro, chloro, bromo or iodo.

In case “R²” represents “halogen” the term means preferably fluoro orchloro and most preferably chloro.

In case “R⁴” represents “halogen” the term means preferably chloro orbromo and most preferably bromo.

In case “halogen” is a substituent to an aryl, a heteroaryl, aheterocyclyl, an aryloxy, a heteroaryloxy, or an aryl-(C₁-C₂)alkoxygroup, the term means fluoro, chloro, bromo or iodo. Preferred examplesare fluoro and chloro.

The term “aryl”, used alone or in any combination, means a phenyl or anaphthyl group. Preferred is a phenyl group. An “optionally substitutedaryl” group means an aryl group as defined before which is unsubstitutedor substituted as explicitly defined.

In case R¹ represents “(C₁-C₄)alkyl which is mono-substituted withoptionally substituted aryl” the term “optionally substituted aryl”means a phenyl or a naphthyl group (preferably phenyl), which groups areindependently unsubstituted, mono-, di- or tri-substituted (preferablyunsubstituted, mono- or di-substituted), wherein the substituents areindependently selected from the group consisting of halogen,(C₁-C₄)alkyl, (C₁-C₄)alkoxy and (C₁-C₂)fluoroalkyl. Preferably thesubstituents are independently selected from the group consisting ofhalogen, (C₁-C₄)alkyl and (C₁-C₄)alkoxy. More preferably thesubstituents are independently selected from the group consisting ofhalogen and (C₁-C₄)alkyl. Examples of such optionally substituted arylgroups are phenyl, naphthyl, 2-fluoro-phenyl, 3-fluoro-phenyl,4-fluoro-phenyl, 2,3-difluoro-phenyl, 2,4-difluoro-phenyl,2,5-difluoro-phenyl, 2,6-difluoro-phenyl, 2-chloro-phenyl,3-chloro-phenyl, 4-chloro-phenyl, 2,3-dichloro-phenyl,2,4-dichloro-phenyl, 2,6-dichloro-phenyl, 2-chloro-5-fluoro-phenyl,5-chloro-2-fluoro-phenyl, 2-methyl-phenyl, 2,3-dimethyl-phenyl,2,4-dimethyl-phenyl and 2-methoxy-phenyl (and especially phenyl,2-fluoro-phenyl, 3-fluoro-phenyl, 4-fluoro-phenyl, 2,3-difluoro-phenyl,2,4-difluoro-phenyl, 2,5-difluoro-phenyl, 2,6-difluoro-phenyl,2-chloro-phenyl, 3-chloro-phenyl, 4-chloro-phenyl, 2,3-dichloro-phenyl,2,6-dichloro-phenyl, 2-chloro-5-fluoro-phenyl, 5-chloro-2-fluoro-phenyl,2,3-dimethyl-phenyl and 2,4-dimethyl-phenyl). In a preferred embodiment,in case Y represents —NH—, the term “optionally substituted aryl”preferably means a phenyl group which is unsubstituted ormono-substituted, wherein the substituent is selected from halogen or(C₁-C₄)alkoxy (especially from fluoro, chloro or methoxy). In anotherpreferred embodiment, in case Y represents —O—, the term “optionallysubstituted aryl” preferably means a phenyl group which isunsubstituted, mono-, di- or tri-substituted (preferably unsubstituted,mono- or di-substituted), wherein the substituents are independentlyselected from the group consisting of halogen, (C₁-C₄)alkyl,(C₁-C₄)alkoxy and (C₁-C₂)fluoroalkyl (and preferably from halogen and(C₁-C₄)alkyl). In still another preferred embodiment, in case Yrepresents a bond, the term “optionally substituted aryl” means a phenylor naphthyl group (preferably phenyl), which groups are independentlyunsubstituted, mono-, di- or tri-substituted (preferably unsubstituted,mono- or di-substituted and most preferably unsubstituted ormono-substituted), wherein the substituents are independently selectedfrom the group consisting of halogen, (C₁-C₄)alkyl, (C₁-C₄)alkoxy and(C₁-C₂)fluoroalkyl (and preferably from halogen and (C₁-C₄)alkyl).

In case R¹ represents “(C₂-C₄)alkenyl which is mono-substituted withoptionally substituted aryl” the term “optionally substituted aryl”means a phenyl or a naphthyl group (preferably phenyl), which groups areindependently unsubstituted, mono-, di- or tri-substituted (preferablyunsubstituted, mono or di-substituted and most preferably mono- ordi-substituted), wherein the substituents are independently selectedfrom the group consisting of halogen, (C₁-C₄)alkyl, (C₁-C₄)alkoxy and(C₁-C₂)fluoroalkyl. Preferably the substituents are independentlyselected from the group consisting of halogen, (C₁-C₄)alkyl and(C₁-C₄)alkoxy and most preferably from halogen. Examples of suchoptionally substituted aryl groups are phenyl, 4-fluoro-phenyl,2,4-difluoro-phenyl, 4-methyl-phenyl and 4-methoxy-phenyl.

In case R¹ represents “(C₃-C₆)cycloalkyl which is mono-substituted withoptionally substituted aryl” the term “optionally substituted aryl”means a phenyl or a naphthyl group (preferably phenyl), which groups areindependently unsubstituted, mono-, di- or tri-substituted (preferablyunsubstituted, mono- or di-substituted and most preferably unsubstitutedor mono-substituted), wherein the substituents are independentlyselected from the group consisting of halogen, (C₁-C₄)alkyl,(C₁-C₄)alkoxy and (C₁-C₂)fluoroalkyl. Preferably the substituents areindependently selected from the group consisting of halogen,(C₁-C₄)alkyl and (C₁-C₂)fluoroalkyl. Examples of such optionallysubstituted aryl groups are phenyl, 3-fluoro-phenyl, 4-fluoro-phenyl,2-chloro-phenyl, 2-methyl-phenyl and 2-trifluoromethyl-phenyl.

The term “aryloxy”, used alone or in combination, refers to an aryl-O—group wherein the aryl group is as defined before. An “optionallysubstituted aryloxy” group means an aryloxy group as defined beforewhich is unsubstituted or substituted as explicitly defined. In case R¹represents “(C₁-C₄)alkyl which is mono-substituted with optionallysubstituted aryloxy” the term “optionally substituted aryloxy” means aphenoxy or a naphthyloxy group (preferably phenoxy), which groups areindependently unsubstituted, mono-, di- or tri-substituted (preferablyunsubstituted or mono-substituted and most preferably mono-substituted),wherein the substituents are independently selected from the groupconsisting of halogen, (C₁-C₄)alkyl, (C₁-C₄)alkoxy and(C₁-C₂)fluoroalkyl. Preferably the substituents are independentlyselected from the group consisting of halogen and (C₁-C₄)alkyl and mostpreferably from halogen. Examples of such optionally substituted aryloxygroups are phenoxy and 4-fluoro-phenoxy.

The term “optionally substituted aryl-(C₁-C₂)alkoxy”, used alone or incombination, refers to an aryl-(C₁-C₂)alkoxy group as defined abovewherein the aryl group is unsubstituted or substituted as explicitlydefined.

In case R¹ represents “(C₁-C₄)alkyl which is mono-substituted withoptionally substituted aryl-(C₁-C₂)alkoxy” the term “optionallysubstituted aryl-(C₁-C₂)alkoxy” means the above-mentioned groups,wherein the term “aryl” means a phenyl or a naphthyl group (preferably aphenyl group). The aryl groups are independently unsubstituted, mono-,di- or tri-substituted (preferably unsubstituted or mono-substituted),wherein the substituents are independently selected from the groupconsisting of halogen, (C₁-C₄)alkyl, (C₁-C₄)alkoxy and(C₁-C₂)fluoroalkyl. Preferably the substituents are independentlyselected from halogen. An example of such aryl group is 2-chloro-phenyl.A preferred example of a aryl-(C₁-C₂)alkoxy group is2-chloro-phenyl-methoxy.

The term “heteroaryl”, used alone or in combination, means a 5- to10-membered monocyclic or bicyclic aromatic ring containing 1, 2 or 3heteroatoms (preferably 1 or 2 heteroatoms) independently selected fromoxygen, nitrogen and sulphur (preferably from oxygen and nitrogen).Examples of such heteroaryl groups are furanyl, oxazolyl, isoxazolyl,oxadiazolyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrrolyl,imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrimidyl, pyridazinyl,pyrazinyl, indolyl, isoindolyl, benzofuranyl, isobenzofuranyl,benzothiophenyl, indazolyl, benzimidazolyl, benzoxazolyl,benzisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl,benzo[2,1,3]oxadiazolyl, benzo[2,1,3]thiadiazolyl,benzo[1,2,3]thiadiazolyl, quinolinyl, isoquinolinyl, cinnolinyl,quinazolinyl, quinoxalinyl and phthalazinyl. Preferred examples of suchheteroaryl groups are isoxazolyl (notably isoxazol-4-yl), pyrazolyl(notably pyrazol-5-yl), pyrazinyl (notably pyrazin-2-yl), indolyl(notably indol-3-yl), indazolyl (notably indazol-1-yl and indazol-3-yl)and benzoxazolyl (notably benzoxazol-2-yl). An “optionally substitutedheteroaryl” group means a heteroaryl group as defined before which isunsubstituted or substituted as explicitly defined.

In case R¹ represents “(C₁-C₄)alkyl which is mono-substituted withoptionally substituted heteroaryl” the term “heteroaryl” means theabove-mentioned groups. Preferred examples of such heteroaryl groups areisoxazolyl (notably isoxazol-4-yl), pyrazolyl (notably pyrazol-5-yl),pyrazinyl (notably pyrazin-2-yl), indolyl (notably indol-3-yl),indazolyl (notably indazol-1-yl and indazol-3-yl) and benzoxazolyl(notably benzoxazol-2-yl). More preferred examples of such heteroarylgroups are pyrazolyl (notably pyrazol-5-yl), indazolyl (notablyindazol-1-yl) and benzoxazolyl (notably benzoxazol-2-yl). Preferredexamples, in case Y represents —O—, are pyrazolyl (notablypyrazol-5-yl), pyrazinyl (notably pyrazin-2-yl), indazolyl (notablyindazol-1-yl) and benzoxazolyl (notably benzoxazol-2-yl). Preferredexamples, in case Y represents a bond, are isoxazolyl (notablyisoxazol-4-yl), indolyl (notably indol-3-yl) and indazolyl (notablyindazol-1-yl and indazol-3-yl); most preferred, in case Y represents abond, are indolyl (notably indol-3-yl) and indazolyl (notablyindazol-1-yl and indazol-3-yl). The heteroaryl groups are independentlyunsubstituted, mono-, di- or tri-substituted (preferably unsubstituted,mono- or di-substituted and most preferably unsubstituted ormono-substituted), wherein the substituents are independently selectedfrom the group consisting of halogen, (C₁-C₄)alkyl and (C₁-C₄)alkoxy.Preferably the substituents are independently selected from the groupconsisting of (C₁-C₄)alkyl and (C₁-C₄)alkoxy. Preferred examples of suchoptionally substituted heteroaryl groups are 3,5-dimethyl-isoxazol-4-yl,1-ethyl-3-methyl-pyrazol-5-yl, pyrazin-2-yl, 1-methyl-indol-3-yl,2-methyl-indol-3-yl, 5-methoxy-indol-3-yl, indazol-1-yl, indazol-3-yland benzoxazol-2-yl. Most preferred examples are1-ethyl-3-methyl-pyrazol-5-yl, pyrazin-2-yl, 1-methyl-indol-3-yl,indazol-1-yl and benzoxazol-2-yl.

The term “heteroaryloxy”, used alone or in combination, refers to anheteroaryl-O— group wherein the heteroaryl group is as defined before.An “optionally substituted heteroaryloxy” group means a heteroaryloxygroup as defined before which is unsubstituted or substituted asexplicitly defined.

In case R¹ represents “(C₁-C₄)alkyl which is mono-substituted withoptionally substituted heteroaryloxy” the term “optionally substitutedheteroaryloxy” means the above-mentioned groups. Preferred are 5- or6-membered monocyclic heteroaryloxy groups containing in the heteroarylmoiety 1, 2 or 3 heteroatoms (preferably 1 or 2 heteroatoms)independently selected from oxygen, nitrogen and sulfur. Examples ofsuch 5- or 6-membered monocyclic heteroaryloxy groups are furanyloxy,oxazolyloxy, isoxazolyloxy, oxadiazolyloxy, thienyloxy, thiazolyloxy,isothiazolyloxy, thiadiazolyloxy, pyrrolyloxy, imidazolyloxy,pyrazolyloxy, triazolyloxy, pyridyloxy, pyrimidyloxy, pyridazinyloxy andpyrazinyloxy. A preferred example of such heteroaryloxy group ispyridyloxy (notably pyridin-3-yloxy). The heteroaryloxy groups areindependently unsubstituted, mono-, di- or tri-substituted (preferablyunsubstituted, mono- or di-substituted and most preferablydi-substituted), wherein the substituents are independently selectedfrom the group consisting of halogen, (C₁-C₄)alkyl and (C₁-C₄)alkoxy(preferably from (C₁-C₄)alkyl). An example of such an optionallysubstituted heteroaryloxy group is 2,6-dimethyl-pyridin-3-yloxy.

The term “heterocyclyl”, used alone or in combination, refers to asaturated monocyclic moiety of 5 to 7 ring members (preferably 5 or 6ring members) containing 1 or 2 heteroatoms (preferably 1 heteroatom)selected from nitrogen, oxygen and sulfur (preferably from nitrogen andoxygen), it being understood that a heterocyclyl group does not contain2 sulfur atoms. The sulfur atom of a heterocyclyl group may be in anoxidised form, i.e. as a sulfoxide or sulfonyl. A heterocyclyl group mayoptionally be annelated to a benzene ring (preferred). An “optionallysubstituted heterocyclyl” group means a heterocyclyl group as definedbefore which is unsubstituted or substituted as explicitly defined.

In case R¹ represents “(C₁-C₄)alkyl which is mono-substituted withoptionally substituted heterocyclyl” the term “heterocyclyl” means theabove-mentioned groups. Examples of such heterocyclyl groups arepyrrolidinyl, imidazolidinyl, oxazolidinyl, thiazolidinyl, piperidinyl,piperazinyl, morpholinyl, thiomorpholinyl, dioxanyl, indolinyl,isoindolinyl, dihydrobenzofuranyl, tetrahydroquinolinyl,tetrahydroisoquinolinyl, tetrahydroquinoxalinyl, chromanyl,isochromanyl, dihydrobenzooxazinyl, dihydrobenzothiazinyl anddihydrobenzodioxinyl. Preferred examples are indolinyl (notablyindolin-1-yl), tetrahydroquinolinyl (notably1,2,3,4-tetrahydroquinolin-1-yl) and isochromanyl (notablyisochroman-1-yl). The heterocyclyl groups are independentlyunsubstituted, mono-, di- or tri-substituted (preferably unsubstituted,mono- or di-substituted and most preferably unsubstituted), wherein thesubstituents are independently selected from the group consisting ofhalogen and (C₁-C₄)alkyl.

2) A further embodiment of the invention relates to compounds accordingto embodiment 1), whereinY represents —NH—, —O— or a bond;Z represents O or S;R¹ represents

-   -   (C₃-C₆)alkyl which is unsubstituted, mono-substituted with        (C₁-C₄)alkoxy, or mono-substituted with fluoro;    -   (C₁-C₄)alkyl which is mono-substituted with (C₄-C₆)cycloalkyl,        unsubstituted cyclopropyl, optionally substituted aryl,        optionally substituted heteroaryl, optionally substituted        heterocyclyl, optionally substituted aryloxy, or optionally        substituted aryl-(C₁-C₂)alkoxy;    -   (C₂-C₄)alkenyl which is mono-substituted with optionally        substituted aryl; or    -   (C₃-C₆)cycloalkyl which is mono-substituted with optionally        substituted aryl or di-substituted with (C₁-C₄)alkyl;        R² represents halogen or cyano;        R³ represents hydrogen or methyl; and        R⁴ represents hydrogen, (C₁-C₄)alkyl, (C₃-C₆)cycloalkyl,        halogen, phenyl, (C₁-C₂)fluoroalkyl, or —NH₂;        and to the salts (in particular pharmaceutically acceptable        salts) of such compounds.        3) A further embodiment of the invention relates to compounds        according to embodiment 1), wherein        Y represents —O— or a bond;        Z represents O;        R¹ represents    -   (C₃-C₆)alkyl which is unsubstituted, mono-substituted with        (C₁-C₄)alkoxy, or mono-substituted with fluoro;    -   (C₁-C₄)alkyl which is mono-substituted with (C₄-C₆)cycloalkyl,        optionally substituted aryl, optionally substituted heteroaryl,        or optionally substituted aryl-(C₁-C₂)alkoxy;    -   (C₂-C₄)alkenyl which is mono-substituted with optionally        substituted aryl; or    -   (C₃-C₆)cycloalkyl which is mono-substituted with optionally        substituted aryl;        R² represents halogen or cyano;        R³ represents hydrogen; and        R⁴ represents hydrogen, methyl, bromo, trifluoromethyl, or —NH₂;        and to the salts (in particular pharmaceutically acceptable        salts) of such compounds.        4) A further embodiment of the invention relates to compounds        according to embodiment 1), wherein        Y represents —NH—;        Z represents O or S;        R¹ represents (C₁-C₄)alkyl which is mono-substituted with        optionally substituted aryl;        R² represents halogen (preferably chloro);        R³ represents hydrogen; and        R⁴ represents hydrogen;        and to the salts (in particular pharmaceutically acceptable        salts) of such compounds.        5) A further embodiment of the invention relates to compounds        according to embodiment 1), wherein        Y represents —O—;        Z represents O;        R¹ represents    -   (C₃-C₆)alkyl which is unsubstituted, mono-substituted with        (C₁-C₄)alkoxy, or mono-, di- or tri-substituted with fluoro; or    -   (C₁-C₄)alkyl which is mono-substituted with (C₄-C₆)cycloalkyl,        optionally substituted aryl, or optionally substituted        heteroaryl;        R² represents halogen or cyano;        R³ represents hydrogen or methyl;        R⁴ represents hydrogen, (C₁-C₄)alkyl, (C₃-C₆)cycloalkyl,        halogen, phenyl, (C₁-C₂)fluoroalkyl, or —NR⁵R⁶;        R⁵ represents hydrogen or methyl; and        R⁶ represents hydrogen, (C₁-C₄)alkyl, (C₁-C₄)alkyl-carbonyl,        (C₁-C₄)alkyl-sulfonyl, (C₃-C₆)cycloalkyl-carbonyl, or        (C₃-C₆)cycloalkyl-sulfonyl;        and to the salts (in particular pharmaceutically acceptable        salts) of such compounds.        6) A further embodiment of the invention relates to compounds        according to embodiment 1), wherein        Y represents —O—;        Z represents O;        R¹ represents    -   (C₃-C₆)alkyl which is unsubstituted, mono-substituted with        (C₁-C₄)alkoxy, or mono-substituted with fluoro; or    -   (C₁-C₄)alkyl which is mono-substituted with (C₄-C₆)cycloalkyl,        optionally substituted aryl, or optionally substituted        heteroaryl;        R² represents halogen or cyano;        R³ represents hydrogen; and        R⁴ represents hydrogen, methyl, bromo, trifluoromethyl, or —NH₂;        and to the salts (in particular pharmaceutically acceptable        salts) of such compounds.        7) A further embodiment of the invention relates to compounds        according to embodiment 1), wherein        Y represents a bond;        Z represents O;        R¹ represents    -   (C₁-C₄)alkyl which is mono-substituted with (C₄-C₆)cycloalkyl,        optionally substituted cyclopropyl, optionally substituted aryl,        optionally substituted heteroaryl, optionally substituted        heterocyclyl, optionally substituted aryloxy, optionally        substituted heteroaryloxy, or optionally substituted        aryl-(C₁-C₂)alkoxy;    -   (C₂-C₄)alkenyl which is mono-substituted with optionally        substituted aryl; or    -   (C₃-C₆)cycloalkyl which is unsubstituted, mono-substituted with        optionally substituted aryl or mono- or di-substituted with        (C₁-C₄)alkyl;        R² represents halogen or cyano (preferably halogen);        R³ represents hydrogen; and        R⁴ represents hydrogen, (C₁-C₄)alkyl, halogen, trifluoromethyl,        or —NH₂ (preferably hydrogen or (C₁-C₄)alkyl);        and to the salts (in particular pharmaceutically acceptable        salts) of such compounds.        8) A further embodiment of the invention relates to compounds        according to embodiment 1), wherein        Y represents a bond;        Z represents O;        R¹ represents    -   (C₁-C₄)alkyl which is mono-substituted with (C₄-C₆)cycloalkyl,        unsubstituted cyclopropyl, optionally substituted aryl,        optionally substituted heteroaryl, optionally substituted        heterocyclyl, optionally substituted aryloxy, or optionally        substituted aryl-(C₁-C₂)alkoxy;    -   (C₂-C₄)alkenyl which is mono-substituted with optionally        substituted aryl; or    -   (C₃-C₆)cycloalkyl which is mono-substituted with optionally        substituted aryl;        R² represents halogen;        R³ represents hydrogen; and        R⁴ represents hydrogen or (C₁-C₄)alkyl;        and to the salts (in particular pharmaceutically acceptable        salts) of such compounds.        9) A further embodiment of the invention relates to compounds        according to embodiment 1), wherein        Y represents a bond;        Z represents O;        R¹ represents cyclopropyl which is mono-substituted with        optionally substituted aryl;        R² represents halogen;        R³ represents hydrogen; and        R⁴ represents hydrogen or methyl;        and to the salts (in particular pharmaceutically acceptable        salts) of such compounds.        10) A further embodiment of the invention relates to compounds        according to any one of embodiments 1) or 2), wherein        Y represents —NH—;        and to the salts (in particular pharmaceutically acceptable        salts) of such compounds.        11) A further embodiment of the invention relates to compounds        according to any one of embodiments 1) to 3), wherein        Y represents —O—;        and to the salts (in particular pharmaceutically acceptable        salts) of such compounds.        12) A further embodiment of the invention relates to compounds        according to any one of embodiments 1) to 3), wherein        Y represents a bond;        and to the salts (in particular pharmaceutically acceptable        salts) of such compounds.        13) A further embodiment of the invention relates to compounds        according to any one of embodiments 1) to 12), wherein        Z represents O;        and to the salts (in particular pharmaceutically acceptable        salts) of such compounds.        14) A further embodiment of the invention relates to compounds        according to any one of embodiments 1), 2) or 10) to 13),        wherein        R¹ represents    -   (C₃-C₆)alkyl which is unsubstituted, mono-substituted with        (C₁-C₄)alkoxy, or mono-, di- or tri-substituted (preferably        mono-substituted) with fluoro;    -   (C₁-C₄)alkyl which is mono-substituted with (C₄-C₆)cycloalkyl,        unsubstituted cyclopropyl, optionally substituted aryl,        optionally substituted heteroaryl, optionally substituted        heterocyclyl, optionally substituted aryloxy, or optionally        substituted aryl-(C₁-C₂)alkoxy;    -   (C₂-C₄)alkenyl which is mono-substituted with optionally        substituted aryl; or    -   (C₃-C₆)cycloalkyl which is mono-substituted with optionally        substituted aryl or di-substituted with (C₁-C₄)alkyl (preferably        mono-substituted with optionally substituted aryl);        and to the salts (in particular pharmaceutically acceptable        salts) of such compounds.        15) A further embodiment of the invention relates to compounds        according to any one of embodiments 1) to 3), 7), 8) or 10) to        13), wherein R¹ represents    -   (C₁-C₄)alkyl (preferably methyl or ethyl) which is        mono-substituted with (C₄-C₆)cycloalkyl, optionally substituted        aryl, or optionally substituted aryl-(C₁-C₂)alkoxy;    -   (C₂-C₄)alkenyl which is mono-substituted with optionally        substituted aryl; or    -   (C₃-C₆)cycloalkyl which is mono-substituted with optionally        substituted aryl;        and to the salts (in particular pharmaceutically acceptable        salts) of such compounds.        16) A further embodiment of the invention relates to compounds        according to any one of embodiments 1) to 3), 5), 6) or 10) to        13), wherein R¹ represents    -   (C₃-C₆)alkyl which is unsubstituted, mono-substituted with        (C₁-C₄)alkoxy, or mono-substituted with fluoro; or    -   (C₁-C₄)alkyl (preferably methyl or ethyl) which is        mono-substituted with (C₄-C₆)cycloalkyl, optionally substituted        aryl, or optionally substituted heteroaryl;        and to the salts (in particular pharmaceutically acceptable        salts) of such compounds.        17) A further embodiment of the invention relates to compounds        according to any one of embodiments 1) to 3), 5), 6) or 10) to        13), wherein        R¹ represents (C₃-C₆)alkyl which is unsubstituted,        mono-substituted with (C₁-C₄)alkoxy, or mono-, di- or        tri-substituted with fluoro (preferably unsubstituted,        mono-substituted with methoxy, or mono-substituted with fluoro);        and to the salts (in particular pharmaceutically acceptable        salts) of such compounds.        18) A further embodiment of the invention relates to compounds        according to any one of embodiments 1), 2), 7), 8) or 10) to        13), wherein        R¹ represents (C₁-C₄)alkyl (preferably methyl or ethyl) which is        mono-substituted with (C₄-C₆)cycloalkyl, optionally substituted        aryl, optionally substituted heteroaryl, optionally substituted        heterocyclyl, optionally substituted aryloxy, or optionally        substituted aryl-(C₁-C₂)alkoxy;        and to the salts (in particular pharmaceutically acceptable        salts) of such compounds.        19) A further embodiment of the invention relates to compounds        according to any one of embodiments 1) to 3), 7), 8) or 10) to        13), wherein        R¹ represents (C₁-C₄)alkyl (preferably methyl or ethyl) which is        mono-substituted with (C₄-C₆)cycloalkyl, optionally substituted        aryl, optionally substituted heteroaryl, or optionally        substituted aryl-(C₁-C₂)alkoxy;        and to the salts (in particular pharmaceutically acceptable        salts) of such compounds.        20) A further embodiment of the invention relates to compounds        according to any one of embodiments 1) to 3), 5) to 8) or 10) to        13), wherein        R¹ represents (C₁-C₄)alkyl (preferably methyl or ethyl) which is        mono-substituted with optionally substituted aryl or optionally        substituted heteroaryl;        and to the salts (in particular pharmaceutically acceptable        salts) of such compounds.        21) A further embodiment of the invention relates to compounds        according to any one of embodiments 1) to 8) or 10) to 13),        wherein        R¹ represents (C₁-C₄)alkyl (preferably methyl or ethyl) which is        mono-substituted with optionally substituted aryl;        and to the salts (in particular pharmaceutically acceptable        salts) of such compounds.        22) A further embodiment of the invention relates to compounds        according to any one of embodiments 1) to 3) or 7) to 13),        wherein        R¹ represents (C₃-C₆)cycloalkyl (preferably cyclopropyl) which        is mono-substituted with optionally substituted aryl;        and to the salts (in particular pharmaceutically acceptable        salts) of such compounds.        23) A further embodiment of the invention relates to compounds        according to any one of embodiments 1) to 22), wherein        R² represents halogen (preferably fluoro or chloro and most        preferably chloro); and to the salts (in particular        pharmaceutically acceptable salts) of such compounds.        24) A further embodiment of the invention relates to compounds        according to any one of embodiments 1) to 23), wherein        R³ represents hydrogen;        and to the salts (in particular pharmaceutically acceptable        salts) of such compounds.        25) A further embodiment of the invention relates to compounds        according to any one of embodiments 1), 2), 5) or 10) to 23),        wherein        R³ represents methyl;        and to the salts (in particular pharmaceutically acceptable        salts) of such compounds.        26) A further embodiment of the invention relates to compounds        according to any one of embodiments 1), 2), 5), 7) or 10) to        25), wherein        R⁴ represents hydrogen, (C₁-C₄)alkyl, halogen, trifluoromethyl,        or —NH₂;        and to the salts (in particular pharmaceutically acceptable        salts) of such compounds.        27) A further embodiment of the invention relates to compounds        according to any one of embodiments 1) to 3), 5) to 7) or 10) to        25), wherein        R⁴ represents hydrogen, methyl, bromo, trifluoromethyl, or —NH₂;        and to the salts (in particular pharmaceutically acceptable        salts) of such compounds.        28) A further embodiment of the invention relates to compounds        according to any one of embodiments 1), 2), 5) or 7) to 25),        wherein        R⁴ represents hydrogen or (C₁-C₄)alkyl (preferably hydrogen or        methyl);        and to the salts (in particular pharmaceutically acceptable        salts) of such compounds.        29) A further embodiment of the invention relates to compounds        according to any one of embodiments 1) to 3), 5) to 7) or 10) to        25), wherein        R⁵ and R⁶ represent hydrogen;        and to the salts (in particular pharmaceutically acceptable        salts) of such compounds.        30) A further embodiment of the invention relates to compounds        according to any one of embodiments 1) to 29), wherein the        absolute configuration of the stereogenic center is as depicted        in formula (I_(St1))

and to the salts (in particular pharmaceutically acceptable salts) ofsuch compounds.31) A further embodiment of the invention relates to compounds accordingto any one of embodiments 1) to 29), wherein the absolute configurationof the stereogenic center is as depicted in formula (I_(St2))

and to the salts (in particular pharmaceutically acceptable salts) ofsuch compounds.32) Preferred compounds of formula (I) as defined in embodiment 1) areselected from the group consisting of:

-   {4-Chloro-2-[5-(2-fluoro-benzylcarbamoyl)-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4-yl]-phenoxy}-acetic    acid;-   {4-Chloro-2-[5-(3-fluoro-benzylcarbamoyl)-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4-yl]-phenoxy}-acetic    acid;-   {4-Chloro-2-[5-(4-fluoro-benzylcarbamoyl)-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4-yl]-phenoxy}-acetic    acid;-   [2-(5-Benzylcarbamoyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4-yl)-4-chloro-phenoxy]-acetic    acid;-   {4-Chloro-2-[(R)-5-((1R,2R)-2-phenyl-cyclopropanecarbonyl)-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4-yl]-phenoxy}-acetic    acid;-   {4-Chloro-2-[(R)-5-((1S,2S)-2-phenyl-cyclopropanecarbonyl)-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4-yl]-phenoxy}-acetic    acid;-   (4-Chloro-2-{(R)-5-[(1R,2R)-2-(3-fluoro-phenyl)-cyclopropanecarbonyl]-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4-yl}-phenoxy)-acetic    acid;-   (4-Chloro-2-{(R)-5-[(1R,2R)-2-(4-fluoro-phenyl)-cyclopropanecarbonyl]-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4-yl}-phenoxy)-acetic    acid;-   (4-Chloro-2-{(R)-5-[(1S,2S)-2-(4-fluoro-phenyl)-cyclopropanecarbonyl]-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4-yl}-phenoxy)-acetic    acid;-   {4-Chloro-2-[(R)-2-methyl-5-((1R,2R)-2-phenyl-cyclopropanecarbonyl)-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4-yl]-phenoxy}-acetic    acid;-   {4-Chloro-2-[(S)-2-methyl-5-((1R,2R)-2-phenyl-cyclopropanecarbonyl)-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4-yl]-phenoxy}-acetic    acid;-   4-(2-Carboxymethoxy-5-chloro-phenyl)-2-trifluoromethyl-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic    acid benzyl ester;-   4-(2-Carboxymethoxy-5-chloro-phenyl)-2-isopropyl-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic    acid benzyl ester;-   4-(2-Carboxymethoxy-5-chloro-phenyl)-2-cyclopropyl-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic    acid benzyl ester;-   4-(2-Carboxymethoxy-5-chloro-phenyl)-2-methyl-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic    acid benzyl ester;-   4-(2-Carboxymethoxy-5-chloro-phenyl)-2-ethyl-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic    acid benzyl ester;-   2-Amino-4-(2-carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic    acid benzyl ester;-   (S)-4-(2-Carboxymethoxy-5-chloro-phenyl)-2-methyl-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic    acid benzyl ester;-   (R)-4-(2-Carboxymethoxy-5-chloro-phenyl)-2-methyl-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic    acid benzyl ester;-   2-Bromo-4-(2-carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic    acid benzyl ester;-   (4-Chloro-2-{5-[3-(4-fluoro-phenoxy)-propionyl]-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4-yl}-phenoxy)-acetic    acid;-   {4-Chloro-2-[trans-5-(2-phenyl-cyclopropanecarbonyl)-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4-yl]-phenoxy}-acetic    acid;-   (4-Chloro-2-{trans-5-[2-(2-trifluoromethyl-phenyl)-cyclopropanecarbonyl]-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4-yl}-phenoxy)-acetic    acid;-   (4-Chloro-2-{trans-5-[2-(2-chloro-phenyl)-cyclopropanecarbonyl]-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4-yl}-phenoxy)-acetic    acid;-   {4-Chloro-2-[trans-5-(2-o-tolyl-cyclopropanecarbonyl)-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4-yl]-phenoxy}-acetic    acid;-   (4-Chloro-2-{5-[3-(5-methoxy-1H-indol-3-yl)-propionyl]-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4-yl}-phenoxy)-acetic    acid;-   (4-Chloro-2-{5-[3-(2-methyl-1H-indol-3-yl)-propionyl]-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4-yl}-phenoxy)-acetic    acid;-   (4-Chloro-2-{5-[3-(1-methyl-1H-indol-3-yl)-propionyl]-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4-yl}-phenoxy)-acetic    acid;-   {4-Chloro-2-[5-(3-o-tolyl-propionyl)-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4-yl]-phenoxy}-acetic    acid;-   (4-Chloro-2-{5-[4-(2-fluoro-phenyl)-butyryl]-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4-yl}-phenoxy)-acetic    acid;-   (4-Chloro-2-{5-[2-(2-chloro-benzyloxy)-acetyl]-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4-yl}-phenoxy)-acetic    acid;-   (4-Chloro-2-{5-[2-(2,6-dimethyl-pyridin-3-yloxy)-acetyl]-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4-yl}-phenoxy)-acetic    acid;-   {4-Chloro-2-[5-(3-indazol-1-yl-propionyl)-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4-yl]-phenoxy}-acetic    acid;-   {4-Chloro-2-[5-(2-phenoxy-acetyl)-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4-yl]-phenoxy}-acetic    acid;-   {4-Chloro-2-[5-((S)-3-phenyl-butyryl)-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4-yl]-phenoxy}-acetic    acid;-   {4-Chloro-2-[5-(indane-2-carbonyl)-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4-yl]-phenoxy}-acetic    acid;-   (4-Chloro-2-{5-[2-(1-phenyl-cyclopropyl)-acetyl]-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4-yl}-phenoxy)-acetic    acid;-   {4-Chloro-2-[5-((R)-3-phenyl-butyryl)-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4-yl]-phenoxy}-acetic    acid;-   {4-Chloro-2-[5-(2-isochroman-1-yl-acetyl)-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4-yl]-phenoxy}-acetic    acid;-   {4-Chloro-2-[5-(3,3-dimethyl-butyryl)-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4-yl]-phenoxy}-acetic    acid;-   {4-Chloro-2-[5-(2-cyclopropyl-acetyl)-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4-yl]-phenoxy}-acetic    acid;-   (4-Chloro-2-{5-[3-(3,5-dimethyl-isoxazol-4-yl)-propionyl]-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4-yl}-phenoxy)-acetic    acid;-   [4-Chloro-2-(5-cyclopropanecarbonyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4-yl)-phenoxy]-acetic    acid;-   {4-Chloro-2-[5-(2-1H-indazol-3-yl-acetyl)-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4-yl]-phenoxy}-acetic    acid;-   (4-Chloro-2-{5-[(E)-(3-phenyl-acryloyl)]-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4-yl}-phenoxy)-acetic    acid;-   {4-Chloro-2-[5-(2-indan-2-yl-acetyl)-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4-yl]-phenoxy}-acetic    acid;-   {4-Chloro-2-[5-(2,2-dimethyl-cyclopropanecarbonyl)-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4-yl]-phenoxy}-acetic    acid;-   {4-Chloro-2-[5-(2-cyclohexyl-acetyl)-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4-yl]-phenoxy}-acetic    acid;-   {4-Chloro-2-[5-(2-naphthalen-2-yl-acetyl)-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4-yl]-phenoxy}-acetic    acid;-   {4-Chloro-2-[5-(2-naphthalen-1-yl-acetyl)-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4-yl]-phenoxy}-acetic    acid;-   (4-Chloro-2-{5-[4-(4-fluoro-phenyl)-butyryl]-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4-yl}-phenoxy)-acetic    acid;-   {4-Chloro-2-[5-(3-2,3-dihydro-indol-1-yl-propionyl)-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4-yl]-phenoxy}-acetic    acid;-   {4-Chloro-2-[5-(3-3,4-dihydro-2H-quinolin-1-yl-propionyl)-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4-yl]-phenoxy}-acetic    acid;-   (4-Chloro-2-{5-[(E)-3-(4-methoxy-phenyl)-acryloyl]-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4-yl}-phenoxy)-acetic    acid;-   (4-Chloro-2-{5-[(E)-3-(4-fluoro-phenyl)-acryloyl]-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4-yl}-phenoxy)-acetic    acid;-   {4-Chloro-2-[5-((E)-3-p-tolyl-acryloyl)-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4-yl]-phenoxy}-acetic    acid;-   (4-Chloro-2-{5-[(E)-3-(2,4-difluoro-phenyl)acryloyl]-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4-yl}-phenoxy)-acetic    acid;-   (R)-4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic    acid 2,5-difluoro-benzyl ester;-   (R)-4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic    acid 2,4-difluoro-benzyl ester;-   (R)-4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic    acid 2,2-dimethyl-butyl ester;-   (R)-4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic    acid 4-fluoro-benzyl ester;-   (R)-4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic    acid 3-methoxy-3-methyl-butyl ester;-   (R)-4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic    acid 2,4-dimethyl-benzyl ester;-   (R)-4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic    acid 2-chloro-5-fluoro-benzyl ester;-   (R)-4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic    acid 3,3-dimethyl-butyl ester;-   (R)-4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic    acid cyclohexylmethyl ester;-   (R)-4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic    acid 3-methyl-butyl ester;-   (R)-4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic    acid 5-chloro-2-fluoro-benzyl ester;-   (R)-4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic    acid cyclobutylmethyl ester;-   (R)-4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic    acid 2-methyl-butyl ester;-   (R)-4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic    acid 2,3-difluoro-benzyl ester;-   (R)-4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic    acid 2,3-dimethyl-benzyl ester;-   (R)-4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic    acid 2,6-difluoro-benzyl ester;-   (R)-4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic    acid 3-fluoro-propyl ester;-   (R)-4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic    acid 2-fluoro-benzyl ester;-   (R)-4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic    acid 3-fluoro-benzyl ester;-   4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic    acid 2-(3-fluoro-phenyl)-ethyl ester;-   4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic    acid 3-fluoro-benzyl ester;-   4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic    acid 2-fluoro-benzyl ester;-   4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic    acid 4-fluoro-benzyl ester;-   4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic    acid 2,3-dichloro-benzyl ester;-   4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic    acid 2,3-difluoro-benzyl ester;-   4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic    acid 2,4-difluoro-benzyl ester;-   4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic    acid 2-chloro-benzyl ester;-   4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic    acid 3-chloro-benzyl ester;-   4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic    acid 4-chloro-benzyl ester;-   4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic    acid 2,6-dichloro-benzyl ester;-   4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic    acid phenethyl ester;-   4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic    acid 2,6-difluoro-benzyl ester;-   4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic    acid indazol-1-ylmethyl ester;-   4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic    acid 2-(2-ethyl-5-methyl-2H-pyrazol-3-yl)-ethyl ester;-   4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic    acid 2-chloro-5-fluoro-benzyl ester;-   4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic    acid 2,5-difluoro-benzyl ester;-   4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic    acid 2,4-dichloro-benzyl ester;-   4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic    acid pyrazin-2-ylmethyl ester;-   4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic    acid cyclohexylmethyl ester;-   4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic    acid benzooxazol-2-ylmethyl ester;-   4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic    acid isobutyl ester;-   4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic    acid butyl ester;-   4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic    acid 2,4-dimethyl-benzyl ester;-   4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic    acid 2,3-dimethyl-benzyl ester;-   4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic    acid 5-chloro-2-fluoro-benzyl ester;-   (R)-4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic    acid benzyl ester;-   (S)-4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic    acid benzyl ester;-   4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic    acid benzyl ester;-   4-(2-Carboxymethoxy-5-cyano-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic    acid benzyl ester;-   [4-Chloro-2-(5-phenethylcarbamoyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4-yl)-phenoxy]-acetic    acid;-   {4-Chloro-2-[5-(2-chloro-benzylcarbamoyl)-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4-yl]-phenoxy}-acetic    acid;-   {4-Chloro-2-[5-(2-m    ethoxy-benzylcarbamoyl)-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4-yl]-phenoxy}-acetic    acid;-   {4-Chloro-2-[5-(2-methoxy-benzylthiocarbamoyl)-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4-yl]-phenoxy}-acetic    acid;-   4-(2-Carboxymethoxy-5-chloro-phenyl)-2-propyl-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic    acid benzyl ester;-   4-(2-Carboxymethoxy-5-chloro-phenyl)-2-phenyl-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic    acid benzyl ester;-   4-(2-Carboxymethoxy-5-chloro-phenyl)-2-methanesulfonylamino-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic    acid benzyl ester;-   4-(2-Carboxymethoxy-5-chloro-phenyl)-2-cyclopropanesulfonylamino-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic    acid benzyl ester;-   4-(2-Carboxymethoxy-5-chloro-phenyl)-2-(cyclopropanecarbonyl-amino)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic    acid benzyl ester;-   2-Acetylamino-4-(2-carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic    acid benzyl ester;-   4-(2-Carboxymethoxy-5-chloro-phenyl)-2-dimethylamino-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic    acid benzyl ester;-   4-(2-Carboxymethoxy-5-fluoro-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic    acid benzyl ester;-   4-[2-((R)-1-Carboxy-ethoxy)-5-chloro-phenyl]-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic    acid benzyl ester; and-   4-[2-((S)-1-Carboxy-ethoxy)-5-chloro-phenyl]-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic    acid benzyl ester;    or salts (in particular pharmaceutically acceptable salts) of such    compounds;    it is to be understood for any of the above listed compounds, that a    stereogenic center, which is not specifically assigned, may be in    absolute (R)- or absolute (S)-configuration and that a double bond,    which is not specifically assigned, may be in (E)- or    (Z)-configuration; for example, the stereogenic center at the    4-position of the 4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridine    core-structure may be in absolute (R)-configuration or absolute    (S)-configuration (and preferably in absolute (R)-configuration).    Notably, compounds containing more than one stereogenic center may    be at each stereogenic center, which is not specifically assigned,    in absolute (R)- or absolute (S)-configuration; for example a    compound listed as    (4-Chloro-2-{trans-5-[2-(2-trifluoromethyl-phenyl)-cyclopropanecarbonyl]-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4-yl}-phenoxy)-acetic    acid may be    (4-Chloro-2-{(R)-5-[(1R,2R)-2-(2-trifluoromethyl-phenyl)-cyclopropanecarbonyl]-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4-yl}-phenoxy)-acetic    acid,    (4-Chloro-2-{(R)-5-[(1S,2S)-2-(2-trifluoromethyl-phenyl)-cyclopropanecarbonyl]-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4-yl}-phenoxy)-acetic    acid,    (4-Chloro-2-{(S)-5-[(1R,2R)-2-(2-trifluoromethyl-phenyl)-cyclopropanecarbonyl]-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4-yl}-phenoxy)-acetic    acid,    (4-Chloro-2-{(S)-5-[(1S,2S)-2-(2-trifluoromethyl-phenyl)-cyclopropanecarbonyl]-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4-yl}-phenoxy)-acetic    acid or a mixture thereof.

It is well understood that the invention relates to compounds accordingto embodiment 1); or according to embodiment 1) limited by the featuresof an embodiment dependent on embodiment 1; or according toembodiment 1) limited by the features of a cascade of dependentembodiments e.g. in the form of “embodiment 3) depending on embodiment2) depending on embodiment 1)”. In case of an embodiment depending onmore than one other embodiment, it is understood that each combinationis specifically disclosed. Also, in case an embodiment is dependent onmore than one other embodiment and one or more of said other embodimentsare themselves dependent on one or more further embodiments, it isunderstood that each combination is specifically disclosed if obtainablewith regard to the given dependencies and multiple dependencies.Notably, embodiments resulting from cascades of more than threeembodiments depending on each other may be construed under observance ofthe given dependencies and multiple dependencies and are thus intendedto be specifically disclosed. Representative examples of embodimentswhich are possible based on the dependencies of the embodiments 1) to32) as disclosed hereinabove and which are therefore intended andherewith specifically disclosed in individualized form are:

1, 2+1, 3+1, 4+1, 5+1, 6+1, 7+1, 8+1, 9+1, 10+2+1, 11+2+1, 12+2+1, 13+1,13+2+1, 13+4+1, 13+10+2+1, 13+11+2+1, 13+12+2+1, 14+13+1, 14+13+2+1,14+13+4+1, 14+13+10+2+1, 14+13+11+2+1, 14+13+12+2+1, 15+2+1, 15+3+1,15+8+1, 15+13+1, 15+13+2+1, 15+13+4+1, 15+13+10+2+1, 15+13+11+2+1,15+13+12+2+1, 16+2+1, 16+3+1, 16+6+1, 16+13+1, 16+13+2+1, 16+13+4+1,16+13+10+2+1, 16+13+11+2+1, 16+13+12+2+1, 17+3+1, 17+13+1, 17+13+2+1,17+13+4+1, 17+13+10+2+1, 17+13+11+2+1, 17+13+12+2+1, 18+13+1, 18+13+2+1,18+13+4+1, 18+13+10+2+1, 18+13+11+2+1, 18+13+12+2+1, 19+3+1, 19+8+1,19+13+1, 19+13+2+1, 19+13+4+1, 19+13+10+2+1, 19+13+11+2+1, 19+13+12+2+1,20+3+1, 20+8+1, 20+13+1, 20+13+2+1, 20+13+4+1, 20+13+10+2+1,20+13+11+2+1, 20+13+12+2+1, 21+3+1, 21+6+1, 21+8+1, 21+13+1, 21+13+2+1,21+13+4+1, 21+13+10+2+1, 21+13+11+2+1, 21+13+12+2+1, 22+3+1, 22+8+1,22+13+1, 22+13+2+1, 22+13+4+1, 22+13+10+2+1, 22+13+11+2+1, 22+13+12+2+1,23+1, 23+2+1, 23+3+1, 23+6+1, 23+13+1, 23+13+2+1, 23+13+4+1,23+13+10+2+1, 23+13+11+2+1, 23+13+12+2+1, 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30+28+15+2+1, 30+28+15+3+1,30+28+15+8+1, 30+28+15+13+1, 30+28+15+13+2+1, 30+28+15+13+4+1,30+28+15+13+10+2+1, 30+28+15+13+11+2+1, 30+28+15+13+12+2+1,30+28+19+3+1, 30+28+19+8+1, 30+28+19+13+1, 30+28+19+13+2+1,30+28+19+13+4+1, 30+28+19+13+10+2+1, 30+28+19+13+11+2+1,30+28+19+13+12+2+1, 30+28+21+3+1, 30+28+21+6+1, 30+28+21+8+1,30+28+21+13+1, 30+28+21+13+2+1, 30+28+21+13+4+1, 30+28+21+13+10+2+1,30+28+21+13+11+2+1, 30+28+21+13+12+2+1, 30+28+23+1, 30+28+23+2+1,30+28+23+3+1, 30+28+23+6+1, 30+28+23+13+1, 30+28+23+13+2+1,30+28+23+13+4+1, 30+28+23+13+10+2+1, 30+28+23+13+11+2+1,30+28+23+13+12+2+1, 30+28+23+16+2+1, 30+28+23+16+3+1, 30+28+23+16+6+1,30+28+23+16+13+1, 30+28+23+16+13+2+1, 30+28+23+16+13+4+1,30+28+23+16+13+10+2+1, 30+28+23+16+13+11+2+1, 30+28+23+16+13+12+2+1,30+28+23+19+3+1, 30+28+23+19+8+1, 30+28+23+19+13+1, 30+28+23+19+13+2+1,30+28+23+19+13+4+1, 30+28+23+19+13+10+2+1, 30+28+23+19+13+11+2+1,30+28+23+19+13+12+2+1, 30+28+23+20+3+1, 30+28+23+20+8+1,30+28+23+20+13+1, 30+28+23+20+13+2+1, 30+28+23+20+13+4+1,30+28+23+20+13+10+2+1, 30+28+23+20+13+11+2+1, 30+28+23+20+13+12+2+1,30+28+23+21+3+1, 30+28+23+21+6+1, 30+28+23+21+8+1, 30+28+23+21+13+1,30+28+23+21+13+2+1, 30+28+23+21+13+4+1, 30+28+23+21+13+10+2+1,30+28+23+21+13+11+2+1, 30+28+23+21+13+12+2+1, 30+28+24+1, 30+28+24+2+1,30+28+24+13+1, 30+28+24+13+2+1, 30+28+24+13+4+1, 30+28+24+13+10+2+1,30+28+24+13+11+2+1, 30+28+24+13+12+2+1, 30+28+24+23+1, 30+28+24+23+2+1,30+28+24+23+3+1, 30+28+24+23+6+1, 30+28+24+23+13+1, 30+28+24+23+13+2+1,30+28+24+23+13+4+1, 30+28+24+23+13+10+2+1, 30+28+24+23+13+11+2+1,30+28+24+23+13+12+2+1, 30+28+24+23+16+2+1, 30+28+24+23+16+3+1,30+28+24+23+16+6+1, 30+28+24+23+16+13+1, 30+28+24+23+16+13+2+1,30+28+24+23+16+13+4+1, 30+28+24+23+16+13+10+2+1,30+28+24+23+16+13+11+2+1, 30+28+24+23+16+13+12+2+1, 30+28+24+23+19+3+1,30+28+24+23+19+8+1, 30+28+24+23+19+13+1, 30+28+24+23+19+13+2+1,30+28+24+23+19+13+4+1, 30+28+24+23+19+13+10+2+1,30+28+24+23+19+13+11+2+1, 30+28+24+23+19+13+12+2+1, 30+28+24+23+20+3+1,30+28+24+23+20+8+1, 30+28+24+23+20+13+1, 30+28+24+23+20+13+2+1,30+28+24+23+20+13+4+1, 30+28+24+23+20+13+10+2+1,30+28+24+23+20+13+11+2+1, 30+28+24+23+20+13+12+2+1, 30+28+24+23+21+3+1,30+28+24+23+21+6+1, 30+28+24+23+21+8+1, 30+28+24+23+21+13+1,30+28+24+23+21+13+2+1, 30+28+24+23+21+13+4+1, 30+28+24+23+21+13+10+2+1,30+28+24+23+21+13+11+2+1, 30+28+24+23+21+13+12+2+1, 31+1, 31+2+1,31+3+1, 31+6+1, 31+8+1, 31+13+1, 31+13+2+1, 31+13+4+1, 31+13+10+2+1,31+13+11+2+1, 31+13+12+2+1, 31+27+1, 31+27+2+1, 31+27+3+1, 31+27+6+1,31+27+13+1, 31+27+13+2+1, 31+27+13+4+1, 31+27+13+10+2+1,31+27+13+11+2+1, 31+27+13+12+2+1, 31+27+16+2+1, 31+27+16+3+1,31+27+16+6+1, 31+27+16+13+1, 31+27+16+13+2+1, 31+27+16+13+4+1,31+27+16+13+10+2+1, 31+27+16+13+11+2+1, 31+27+16+13+12+2+1,31+27+19+3+1, 31+27+19+8+1, 31+27+19+13+1, 31+27+19+13+2+1,31+27+19+13+4+1, 31+27+19+13+10+2+1, 31+27+19+13+11+2+1,31+27+19+13+12+2+1, 31+27+21+3+1, 31+27+21+6+1, 31+27+21+8+1,31+27+21+13+1, 31+27+21+13+2+1, 31+27+21+13+4+1, 31+27+21+13+10+2+1,31+27+21+13+11+2+1, 31+27+21+13+12+2+1, 31+27+23+1, 31+27+23+2+1,31+27+23+3+1, 31+27+23+6+1, 31+27+23+13+1, 31+27+23+13+2+1,31+27+23+13+4+1, 31+27+23+13+10+2+1, 31+27+23+13+11+2+1,31+27+23+13+12+2+1, 31+27+23+16+2+1, 31+27+23+16+3+1, 31+27+23+16+6+1,31+27+23+16+13+1, 31+27+23+16+13+2+1, 31+27+23+16+13+4+1,31+27+23+16+13+10+2+1, 31+27+23+16+13+11+2+1, 31+27+23+16+13+12+2+1,31+27+23+19+3+1, 31+27+23+19+8+1, 31+27+23+19+13+1, 31+27+23+19+13+2+1,31+27+23+19+13+4+1, 31+27+23+19+13+10+2+1, 31+27+23+19+13+11+2+1,31+27+23+19+13+12+2+1, 31+27+23+20+3+1, 31+27+23+20+8+1,31+27+23+20+13+1, 31+27+23+20+13+2+1, 31+27+23+20+13+4+1,31+27+23+20+13+10+2+1, 31+27+23+20+13+11+2+1, 31+27+23+20+13+12+2+1,31+27+23+21+3+1, 31+27+23+21+6+1, 31+27+23+21+8+1, 31+27+23+21+13+1,31+27+23+21+13+2+1, 31+27+23+21+13+4+1, 31+27+23+21+13+10+2+1,31+27+23+21+13+11+2+1, 31+27+23+21+13+12+2+1, 31+27+24+1, 31+27+24+2+1,31+27+24+13+1, 31+27+24+13+2+1, 31+27+24+13+4+1, 31+27+24+13+10+2+1,31+27+24+13+11+2+1, 31+27+24+13+12+2+1, 31+27+24+23+1, 31+27+24+23+2+1,31+27+24+23+3+1, 31+27+24+23+6+1, 31+27+24+23+13+1, 31+27+24+23+13+2+1,31+27+24+23+13+4+1, 31+27+24+23+13+10+2+1, 31+27+24+23+13+11+2+1,31+27+24+23+13+12+2+1, 31+27+24+23+16+2+1, 31+27+24+23+16+3+1,31+27+24+23+16+6+1, 31+27+24+23+16+13+1, 31+27+24+23+16+13+2+1,31+27+24+23+16+13+4+1, 31+27+24+23+16+13+10+2+1,31+27+24+23+16+13+11+2+1, 31+27+24+23+16+13+12+2+1, 31+27+24+23+19+3+1,31+27+24+23+19+8+1, 31+27+24+23+19+13+1, 31+27+24+23+19+13+2+1,31+27+24+23+19+13+4+1, 31+27+24+23+19+13+10+2+1,31+27+24+23+19+13+11+2+1, 31+27+24+23+19+13+12+2+1, 31+27+24+23+20+3+1,31+27+24+23+20+8+1, 31+27+24+23+20+13+1, 31+27+24+23+20+13+2+1,31+27+24+23+20+13+4+1, 31+27+24+23+20+13+10+2+1,31+27+24+23+20+13+11+2+1, 31+27+24+23+20+13+12+2+1, 31+27+24+23+21+3+1,31+27+24+23+21+6+1, 31+27+24+23+21+8+1, 31+27+24+23+21+13+1,31+27+24+23+21+13+2+1, 31+27+24+23+21+13+4+1, 31+27+24+23+21+13+10+2+1,31+27+24+23+21+13+11+2+1, 31+27+24+23+21+13+12+2+1, 31+28+1, 31+28+2+1,31+28+8+1, 31+28+13+1, 31+28+13+2+1, 31+28+13+4+1, 31+28+13+10+2+1,31+28+13+11+2+1, 31+28+13+12+2+1, 31+28+15+2+1, 31+28+15+3+1,31+28+15+8+1, 31+28+15+13+1, 31+28+15+13+2+1, 31+28+15+13+4+1,31+28+15+13+10+2+1, 31+28+15+13+11+2+1, 31+28+15+13+12+2+1,31+28+19+3+1, 31+28+19+8+1, 31+28+19+13+1, 31+28+19+13+2+1,31+28+19+13+4+1, 31+28+19+13+10+2+1, 31+28+19+13+11+2+1,31+28+19+13+12+2+1, 31+28+21+3+1, 31+28+21+6+1, 31+28+21+8+1,31+28+21+13+1, 31+28+21+13+2+1, 31+28+21+13+4+1, 31+28+21+13+10+2+1,31+28+21+13+11+2+1, 31+28+21+13+12+2+1, 31+28+23+1, 31+28+23+2+1,31+28+23+3+1, 31+28+23+6+1, 31+28+23+13+1, 31+28+23+13+2+1,31+28+23+13+4+1, 31+28+23+13+10+2+1, 31+28+23+13+11+2+1,31+28+23+13+12+2+1, 31+28+23+16+2+1, 31+28+23+16+3+1, 31+28+23+16+6+1,31+28+23+16+13+1, 31+28+23+16+13+2+1, 31+28+23+16+13+4+1,31+28+23+16+13+10+2+1, 31+28+23+16+13+11+2+1, 31+28+23+16+13+12+2+1,31+28+23+19+3+1, 31+28+23+19+8+1, 31+28+23+19+13+1, 31+28+23+19+13+2+1,31+28+23+19+13+4+1, 31+28+23+19+13+10+2+1, 31+28+23+19+13+11+2+1,31+28+23+19+13+12+2+1, 31+28+23+20+3+1, 31+28+23+20+8+1,31+28+23+20+13+1, 31+28+23+20+13+2+1, 31+28+23+20+13+4+1,31+28+23+20+13+10+2+1, 31+28+23+20+13+11+2+1, 31+28+23+20+13+12+2+1,31+28+23+21+3+1, 31+28+23+21+6+1, 31+28+23+21+8+1, 31+28+23+21+13+1,31+28+23+21+13+2+1, 31+28+23+21+13+4+1, 31+28+23+21+13+10+2+1,31+28+23+21+13+11+2+1, 31+28+23+21+13+12+2+1, 31+28+24+1, 31+28+24+2+1,31+28+24+13+1, 31+28+24+13+2+1, 31+28+24+13+4+1, 31+28+24+13+10+2+1,31+28+24+13+11+2+1, 31+28+24+13+12+2+1, 31+28+24+23+1, 31+28+24+23+2+1,31+28+24+23+3+1, 31+28+24+23+6+1, 31+28+24+23+13+1, 31+28+24+23+13+2+1,31+28+24+23+13+4+1, 31+28+24+23+13+10+2+1, 31+28+24+23+13+11+2+1,31+28+24+23+13+12+2+1, 31+28+24+23+16+2+1, 31+28+24+23+16+3+1,31+28+24+23+16+6+1, 31+28+24+23+16+13+1, 31+28+24+23+16+13+2+1,31+28+24+23+16+13+4+1, 31+28+24+23+16+13+10+2+1,31+28+24+23+16+13+11+2+1, 31+28+24+23+16+13+12+2+1, 31+28+24+23+19+3+1,31+28+24+23+19+8+1, 31+28+24+23+19+13+1, 31+28+24+23+19+13+2+1,31+28+24+23+19+13+4+1, 31+28+24+23+19+13+10+2+1,31+28+24+23+19+13+11+2+1, 31+28+24+23+19+13+12+2+1, 31+28+24+23+20+3+1,31+28+24+23+20+8+1, 31+28+24+23+20+13+1, 31+28+24+23+20+13+2+1,31+28+24+23+20+13+4+1, 31+28+24+23+20+13+10+2+1,31+28+24+23+20+13+11+2+1, 31+28+24+23+20+13+12+2+1, 31+28+24+23+21+3+1,31+28+24+23+21+6+1, 31+28+24+23+21+8+1, 31+28+24+23+21+13+1,31+28+24+23+21+13+2+1, 31+28+24+23+21+13+4+1, 31+28+24+23+21+13+10+2+1,31+28+24+23+21+13+11+2+1, 31+28+24+23+21+13+12+2+1, and 32+1;wherein the list above is not to be construed as limiting with respectto further embodiments which are also possible based on the dependenciesof the embodiments 1) to 32) as disclosed hereinabove and which are alsointended. In the list above the numbers refer to the embodimentsaccording to their numbering provided hereinabove whereas “+” indicatesthe dependency from another embodiment. The different individualizedembodiments are separated by commas. In other words, “10+2+1” forexample refers to embodiment 10) depending on embodiment 2) depending onembodiment 1), i.e. embodiment “10+2+1” corresponds to embodiment 1)further limited by the features of embodiments 2) and 10).

Unless explicitly stated otherwise, the general terms and names usedhereinbefore and hereinafter preferably have within the context of thisdisclosure the following meanings: Where the plural form is used forcompounds, salts, pharmaceutical compositions, diseases and the like,this is intended to mean also a single compound, salt, pharmaceuticalcomposition, disease or the like.

The term “pharmaceutically acceptable salts” refers to non-toxic,inorganic or organic acid and/or base addition salts. Reference can bemade to “Salt selection for basic drugs”, Int. J. Pharm. (1986), 33,201-217.

The compounds of formula (I) according to any one of embodiments 1) to32), or pharmaceutically acceptable salts thereof, may be used for thepreparation of a medicament, and are suitable for the prevention and/ortreatment of diseases selected from the group consisting of chronic andacute allergic/immune diseases/disorders, comprising asthma, allergicasthma, eosinophilic asthma, severe asthma, rhinitis, allergic rhinitis,angioedema, insect venom allergy, drug allergies, allergic sinusitis,allergic nephritis, allergic conjunctivitis, atopic dermatitis,bronchial asthma, food allergy, systemic mast cell disorders,anaphylactic shock, urticaria, eczema, ulcerative colitis, chronicobstructive pulmonary disease (COPD), inflammatory bowel disease andrheumatoid arthritis; eosinophil-related diseases comprising smallvessel vasculitides like Churg-Strauss syndrome, Wegener'sgranulomatosis, microscopic polyangiitis (and organ-specific subsets ofthe latter), hypereosinophilic syndromes like eosinophilic pneumonia,eosinophilic esophagitis, reflux esophagitis, eosinohilic endocarditis(Loeffler's endocarditis), eosinophilia-myalgia syndrome, eosinophilicfasciitis, eosinohilic pustular folliculitis (Ofuji's disease),eosinophilic ulcers, angiolymphoid hyperplasia with eosinophilia (ALHE),eosinophilic cellulitis (Wells syndrome), chronic eosinophilic leukemiaand DRESS syndrome (Drug Rash with Eosinophilia and Systemic Symptoms);and basophil-related diseases, comprising basophilic leukemia andbasophilic leukocytosis.

In a preferred embodiment, the compounds of formula (I) according to anyone of embodiments 1) to 32), or pharmaceutically acceptable saltsthereof, may be used for the preparation of a medicament, and aresuitable for the prevention and/or treatment of diseases selected fromthe group consisting of asthma, allergic asthma, eosinophilic asthma,severe asthma, allergic rhinitis, angioedema, insect venom allergy, drugallergies, allergic sinusitis, allergic nephritis, allergicconjunctivitis, atopic dermatitis, food allergy, systemic mast celldisorders, anaphylactic shock, urticaria and eczema.

In another preferred embodiment, the compounds of formula (I) accordingto any one of embodiments 1) to 32), or pharmaceutically acceptablesalts thereof, may be used for the preparation of a medicament, and aresuitable for the prevention and/or treatment of diseases selected fromthe group consisting of eosinophil-related diseases comprising smallvessel vasculitides like Churg-Strauss syndrome, Wegener'sgranulomatosis, microscopic polyangiitis (and organ-specific subsets ofthe latter), hypereosinophilic syndromes like eosinophilic pneumonia,eosinophilic esophagitis, reflux esophagitis, eosinohilic endocarditis(Loeffler's endocarditis), eosinophilia-myalgia syndrome, eosinophilicfasciitis, eosinohilic pustular folliculitis (Ofuji's disease),eosinophilic ulcers, angiolymphoid hyperplasia with eosinophilia (ALHE),eosinophilic cellulitis (Wells syndrome), chronic eosinophilic leukemiaand DRESS syndrome (Drug Rash with Eosinophilia and Systemic Symptoms).

In yet another preferred embodiment, the compounds of formula (I)according to any one of embodiments 1) to 32), or pharmaceuticallyacceptable salts thereof, may be used for the preparation of amedicament, and are suitable for the prevention and/or treatment ofdiseases selected from the group consisting of basophil-relateddiseases, comprising basophilic leukemia and basophilic leukocytosis.

In a more preferred embodiment, the compounds of formula (I) accordingto any one of embodiments 1) to 32), or pharmaceutically acceptablesalts thereof, may be used for the preparation of a medicament, and aresuitable for the prevention and/or treatment of diseases selected fromone, several or all of the following groups of diseases and disorders:

-   -   1) asthma, allergic asthma, eosinophilic asthma, severe asthma;    -   2) allergic rhinitis;    -   3) eosinophilic esophagitis; and    -   4) atopic dermatitis.

The invention also relates to the use of a compound of formula (I)according to any one of embodiments 1) to 32) for the preparation ofpharmaceutical compositions for the treatment and/or prophylaxis of theabove-mentioned diseases.

The present invention also relates to pharmaceutically acceptable saltsand to pharmaceutical compositions and formulations of compounds offormula (I) according to any one of embodiments 1) to 32).

A pharmaceutical composition according to the present invention containsat least one compound of formula (I) according to any one ofembodiments 1) to 32) (or a pharmaceutically acceptable salt thereof) asthe active agent and optionally carriers and/or diluents and/oradjuvants.

The compounds of formula (I) according to any one of embodiments 1) to32) and their pharmaceutically acceptable salts can be used asmedicaments, e.g. in the form of pharmaceutical compositions for enteral(such as especially oral) or parenteral (including topical applicationor inhalation) administration.

The production of the pharmaceutical compositions can be effected in amanner which will be familiar to any person skilled in the art (see forexample Remington, The Science and Practice of Pharmacy, 21st Edition(2005), Part 5, “Pharmaceutical Manufacturing” [published by LippincottWilliams & Wilkins]) by bringing the described compounds of formula (I)or their pharmaceutically acceptable salts, optionally in combinationwith other therapeutically valuable substances, into a galenicaladministration form together with suitable, non-toxic, inert,therapeutically compatible solid or liquid carrier materials and, ifdesired, usual pharmaceutical adjuvants.

The present invention also relates to a method for the prevention ortreatment of a disease or disorder mentioned herein comprisingadministering to a subject a pharmaceutically active amount of acompound of formula (I) according to any one of embodiments 1) to 32),or a pharmaceutically acceptable salt thereof.

The present invention also includes isotopically labelled, especially ²H(deuterium) labelled compounds of formula (I), which compounds areidentical to the compounds of formula (I) except that one or more atomshave each been replaced by an atom having the same atomic number but anatomic mass different from the atomic mass usually found in nature.Isotopically labelled, especially ²H (deuterium) labelled compounds offormula (I) and salts thereof are within the scope of the presentinvention. Substitution of hydrogen with the heavier isotope ²H(deuterium) may lead to greater metabolic stability, resulting e.g. inincreased in-vivo half-life or reduced dosage requirements, or may leadto reduced inhibition of cytochrome P450 enzymes, resulting e.g. in animproved safety profile. In one embodiment of the invention, thecompounds of formula (I) are not isotopically labelled, or they arelabelled only with one or more deuterium atoms. In a sub-embodiment, thecompounds of formula (I) are not isotopically labelled at all.Isotopically labelled compounds of formula (I) may be prepared inanalogy to the methods described hereinafter, but using the appropriateisotopic variation of suitable reagents or starting materials.

Any reference to a compound of formula (I), (I_(St1)) or (I_(St2)) inthis text is to be understood as referring also to the salts (andespecially the pharmaceutically acceptable salts) of such compounds, asappropriate and expedient. The preferences indicated for the compoundsof formula (I) of course apply mutatis mutandis to the compounds offormula (I_(St1)) and the compounds of formula (I_(St2)) as well as tothe salts and pharmaceutically acceptable salts of the compounds offormula (I), of formula (I_(St1)) or of formula (I_(St2)). The sameapplies to these compounds as medicaments, to pharmaceuticalcompositions containing these compounds as active principles or to theuses of these compounds for the manufacture of a medicament for thetreatment of the diseases according to this invention.

Unless used regarding temperatures, the term “about” (or alternatively“around”) placed before a numerical value “X” refers in the currentapplication to an interval extending from X minus 10% of X to X plus 10%of X, and preferably to an interval extending from X minus 5% of X to Xplus 5% of X. In the particular case of temperatures, the term “about”(or alternatively “around”) placed before a temperature “Y” refers inthe current application to an interval extending from the temperature Yminus 10° C. to Y plus 10° C., and preferably to an interval extendingfrom Y minus 5° C. to Y plus 5° C. Besides, the term “room temperature”(r.t.) as used herein refers to a temperature of about 25° C.

Whenever the word “between” is used to describe a numerical range, it isto be understood that the end points of the indicated range areexplicitly included in the range. For example: if a temperature range isdescribed to be between 40° C. and 80° C., this means that the endpoints 40° C. and 80° C. are included in the range or if a variable isdefined as being an integer between 1 and 4, this means that thevariable is the integer 1, 2, 3, or 4.

As mentioned earlier, compounds of formula (I) modulate the PGD₂activation of the CRTH2 receptor. The biological effect of suchcompounds may be tested in a variety of in vitro, ex vivo and in vivoassays. The ability of the compounds of formula (I) to bind to the CRTH2receptor may be measured by methods similar to those described in theliterature (Arimura A. et al., J. Pharmacol. Exp. Ther. 2001, 298(2),411-419; and Sawyer N. et al., Br. J. Pharmacol, 2002, 137, 1163-1172,respectively) and by the assays described below in the experimentalpart.

A further aspect of the invention is a process for the preparation ofcompounds of formula (I). Compounds according to formula (I) of thepresent invention can be prepared according to the sequence of reactionsoutlined in the schemes below wherein Y, Z, R¹, R², R³, R⁴, R⁵ and R⁶are as defined for formula (I). Other abbreviations used are defined inthe experimental section. In some instances the generic groups Y, Z, R¹,R², R³, R⁴, R⁵ and R⁶ might be incompatible with the assemblyillustrated in the schemes below and, therefore, will require the use ofprotecting groups (PG). For example it may be necessary to protectreactive functional groups such as hydroxy, amino, imino, thio orcarboxy groups, where these are desired in the final product, to avoidtheir unwanted participation in the reactions. The use of protectinggroups is well known in the art (see for example “Protective Groups inOrganic Synthesis”, T. W. Greene, P. G. M. Wuts, Wiley-Interscience,1999). It will be assumed that such protecting groups are as necessaryin place. In the following description, for example, “PG”, when used asamino-protecting group, preferably refers to a group such astert-butoxycarbonyl, benzyloxycarbonyl, or allyloxycarbonyl, mostpreferably benzyloxycarbonyl. Further, “L” refers to a leaving group,such as an activated hydroxy group (for examples as mesylate, tosylateetc.), an in-situ activated hydroxy group (as used, for instance, inMitsunobu reactions), or a halogen, in particular chloro or bromo.Further, “R” refers to a (C₁-C₄)alkyl group, preferably methyl, ethyl ortert-butyl.

In general, all chemical transformations can be performed according towell-known standard methodologies as described in the literature or asdescribed in the procedures below. The compounds obtained may also beconverted into pharmaceutically acceptable salts thereof in a mannerknown per se.

Generally, compounds of Formula (I) are obtained from an ester ofStructure 1, wherein R represents (C₁-C₄)alkyl (preferably methyl,ethyl, or tert-butyl) by hydrolysis of the ester group using routineprocedures, for example by stirring an intermediate of Structure 1,wherein R represents methyl or ethyl, with an aqueous solution of LiOH,NaOH or KOH in an organic co-solvent such as an alcohol (like MeOH orEtOH), THF, acetone, MeCN, or DMF; or by stirring an intermediate ofStructure 1, wherein R represents tert.-butyl, in an acid like TFA.

-   -   Ester of Structure 1, wherein R represents (C₁-C₄)alkyl

An intermediate of Structure 1 is for instance obtained by reacting anintermediate of Structure 2, or a salt thereof, such as a hydrochloridesalt, with a reagent of Formula L-C(O)Y—R¹, wherein Y and R¹ are asdefined for Formula (I) and L is a leaving group such as an halogen (inparticular chloro), in the presence of a base like NEt₃, DIPEA,N-ethyl-morpholine, N-methylpiperidine, or pyridine, in a suitablesolvent, such as THF, or DCM. The starting material L-C(O)Y—R¹ may be achloroformate; an acyl anhydride; or an acyl halide like an acidchloride or an acid bromide. The acyl halide may be commerciallyavailable, known in the art, or obtainable in situ from thecorresponding commercially available or well known carboxylic acid in areaction with a halogenating reagent like oxalyl chloride or phosphorousoxychloride under conditions known to a skilled person.

In another aspect, an intermediate of Structure 2 is reacted with acommercially available or well known isocyanate or isothiocyanate in thepresence of a base to form an intermediate of Structure 1.

In another aspect, an intermediate of Structure 2 is activated withtriphosgene, CDI, or the like and the reactive intermediate is thentreated with an alcohol R¹—OH or an amine R¹—NH₂ to give an intermediateof Structure 1, wherein Y represents —O— or —NH—, respectively.

In a further aspect, an intermediate of Structure 2 is condensed with acommercially available or well known carboxylic acid in the presence ofa coupling reagent, such as EDC, TBTU, diisopropylcarbodiimide, HATU,DCC, Ghosez's reagent or the like, in the presence of a base like NEt₃,DIPEA, or pyridine to form an intermediate of Structure 1. In anotheraspect an intermediate of Structure 2 is reacted with a carbonate 3(wherein R^(A) represents optional substituents to an aryl group) in thepresence of a base like NEt₃ or DIPEA to give an intermediate ofStructure 1-A (Scheme 1). A carbonate 3 is prepared by reaction of abenzyl alcohol 4 with N,N′-disuccinimidyl carbonate in the presence of abase like DMAP.

Alternatively an intermediate of Structure 2 is condensed with4-nitrophenyl chloroformate in the presence of a base like NEt₃ or DIPEAto give a carbamate 5 (Scheme 2). The carbamate 5 is then treated withan alcohol R^(B)OH (wherein R^(B) represents (C₃-C₆)alkyl which isunsubstituted, mono-substituted with (C₁-C₄)alkoxy, or mono-substitutedwith fluoro; or (C₁-C₄)alkyl which is mono-substituted with(C₄-C₆)cycloalkyl, optionally substituted cyclopropyl, optionallysubstituted aryl, optionally substituted heteroaryl, optionallysubstituted heterocyclyl, optionally substituted aryloxy, optionallysubstituted heteroaryloxy, optionally substituted aryl-(C₁-C₂)alkoxy; or(C₃-C₆)cycloalkyl which is unsubstituted, mono-substituted withoptionally substituted aryl or mono- or di-substituted with(C₁-C₄)alkyl) in the presence of potassium tert-butoxide to give acompound of Formula (I-A). Under these specific conditions, thesaponification and the substitution take place during the same reaction.

An intermediate of Structure 2 is obtained after removal of a protectinggroup (PG) from an intermediate of Structure 6, applying reactionconditions known to a skilled person. Preferably, PG is a group such astert-butoxycarbonyl or benzyloxycarbonyl. A benzyloxycarbonyl protectinggroup is removed by hydrogenolysis or treatment with an acid; atert-butoxycarbonyl group is cleaved under acidic conditions.

An intermediate of Structure 6 is obtained by one of the syntheticpathway described below. For example, heating a derivative 7a (whereinR^(C) is —CHR³—COOR) in a solvent like THF and in the presence of analkyl nitrite, like isoamyl nitrite or tert-butyl nitrite, gives acompound of Structure 6-A (Scheme 3). Under the same conditions, theaminothiazole 7b, wherein R^(C) is a protecting group PG² such as anallyl group, is converted into the thiazole 8. Selective deprotection ofthe phenol protecting group PG² of 8, like a selective removal of anallyl group in the presence of a carbamate protecting group PG¹ (liketert-butoxycarbonyl or benzyloxycarbonyl) with Pd(PPh₃)₄ and abarbituric acid derivative and a subsequent alkylation of the resultingphenol 9 with an electrophile L-CHR³—COOR, wherein R³ is as defined inFormula (I) and L is a leaving group such as bromide, in the presence ofa base like Cs₂CO₃ or K₂CO₃ yields an intermediate of Structure 6-A(Scheme 3).

In another aspect, Sandmeyer reaction of the aminothiazole 7a (whereinR^(C) is —CHR³—COOR and PG¹ is tert-butoxycarbonyl or benzyloxycarbonyl)in the presence of copper(II)bromide and an alkyl nitrite, liketert-butyl nitrite, affords a bromothiazole 10 (Scheme 4). The ester 10can then be saponified, for example by treatment with aqueous NaOH in asolvent like DMF. The resulting bromide undergoes a nucleophilicsubstitution upon heating in the presence of a secondary amine(R^(D))₂NH (wherein R^(D) represents (C₁-C₄)alkyl) to give a compound ofFormula I-B. Alternatively, a Neghishi cross-coupling between thebromothiazole 10 and a zinc bromide derivative R^(E)ZnBr or a dialkylzinc derivative R^(E)ZnR^(E) (wherein R^(E) represents (C₁-C₄)alkyl or(C₃-C₆)cycloalkyl) in the presence of a palladium catalyst likePd(PPh₃)₄ affords a compound of Structure 6-B. In another aspect, Suzukicross-coupling between the bromothiazole 10 and a boronic acidR^(F)—B(OH)₂ (wherein R^(F) represents optionally substituted aryl) inthe presence of a base like Na₂CO₃ and a palladium catalyst likePd(PPh₃)₄ yields a compound of Structure 6-C. Finally, treatment of thebromothiazole 10 with methyl 2,2-difluoro-2-(fluorosulfonyl)acetate inthe presence of copper(I)iodide, a palladium catalyst like Pd₂dba₃, anda ligand like AsPh₃, in a solvent like DMF gives a trifluoromethylderivative of Structure 6-D.

In a further aspect, an aminothiazole 7a (wherein R^(C) is —CHR³—COOR)can be converted into an amide of Structure 6-E upon treatment with anacyl chloride R^(G)COCl (wherein R^(G) represents (C₁-C₄)alkyl or(C₃-C₆)cycloalkyl) in the presence of a base like NEt₃. Alternatively,the amino derivative 7a can be treated with a sulfonyl chlorideR^(H)SO₂Cl (wherein R^(H) represents (C₁-C₄)alkyl or (C₃-C₆)cycloalkyl)to give a sulfonamide of Structure 6-F (Scheme 5).

An intermediate 11a (wherein R^(C) is —CHR³—COOR) or 11b (wherein R^(C)is a protecting group PG² such as an allyl group) is obtained via aPictet-Spengler reaction between the salt 12 and the aldehyde 13a or 13bin the presence of a base like NEt₃, a solvent like EtOH, and heating.The resulting aminothiazole 11a or 11b is treated with a protectinggroup precursor PG¹L such as di-tert-butyl dicarbonate or achloroformate (like benzyl chloroformate) in the presence of a base likeNEt₃ to give a compound 7a or 7b. The aldehydes 13a are obtained byalkylation of the corresponding phenols 14 with an electrophileL-CHR³—COOR, wherein R³ is as defined in Formula (I) and L is a leavinggroup such as a bromide. The aldehydes 13b are prepared by alkylation ofthe corresponding phenols 14 with a protecting group precursor PG²L suchas an allyl halide (e.g. PG²L=allyl chloride) or a benzyl halide (e.g.PG²L=benzyl bromide), in the presence of a base like Cs₂CO₃ or K₂CO₃(Scheme 6).

In another aspect, a compound of Structure 6-G can be obtained throughprotection of the secondary amine 15 with a protecting group precursorPGL such as di-tert-butyl dicarbonate or a chloroformate (like benzylchloroformate) in the presence of a base like NEt₃. Compound 15 isobtained through a Bischler-Napieralski reaction by heating the amide 16in a dehydrating agent like POCl₃, followed by reduction of theresulting imine with NaBH₄. The amide 16 is obtained through an amidecoupling between the commercially available amine 17 and the acid 18 inthe presence of coupling reagents like EDC and HOBT and a base likeNEt₃, followed by a phenol alkylation with an electrophile L-CHR³—COOR,wherein R³ is as defined in Formula (I) and L is a leaving group such asbromide, in the presence of a base like Cs₂CO₃ or K₂CO₃ (Scheme 7).

Experimental Section Abbreviations As Used Herein

-   AcOEt Ethyl acetate-   AcOH Acetic acid-   aq. aqueous-   BSA Bovine Serum Albumin-   Bu n-butyl-   ca. circa (latin)—about-   Cbz Benzyloxycarbonyl-   CC Column chromatography on silica gel-   CDI Carbonyldiimidazole-   comb. combined-   conc. Concentrated-   dba Dibenzylideneacetone-   DAD diode array detector-   DCC 1,3-Dicyclohexylcarbodiimide-   DCM Dichloromethane-   DIPEA N,N-Diisopropylethylamine-   DMAP N,N-Dimethyl-4-aminopyridine-   DMF Dimethylformamide-   DMSO Dimethylsulfoxide-   dpm decays per minute-   EDTA Ethylene Diamine Tetraacetic Acid-   EDC 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide-   ee enantiomeric excess-   ELSD evaporative light-scattering detection-   eq. Equivalent-   EtOH ethanol-   ESI-MS Electrospray Ionization Mass Spectroscopy-   Ghosez's reagent 1-Chloro-N,N,2-trimethyl-1-propenylamine-   h hour(s)-   HATU O-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium    hexafluorophosphate-   HPLC High Performance Liquid Chromatography-   HSA human serum albumin-   hv high vacuum-   iPr isopropyl-   L liter(s)-   LC-MS Liquid Chromatography-Mass Spectroscopy-   M molarity [mol L⁻¹]-   Me Methyl-   MeCN Acetonitrile-   MeI Methyl iodide-   MeOH Methanol-   mesyl Methanesulfonyl-   min minute(s)-   MS Mass Spectroscopy-   MW Molecular Weight-   N Normality of solution-   NEt₃ Triethylamine-   NMR Nuclear magnetic resonance-   org. organic-   PBS Phosphate Buffered Saline-   PDA photodiode array-   PG Protecting Group-   PGD₂ Prostaglandin D₂-   prep. preparative-   r.t. room temperature-   s second(s)-   sat. saturated-   Si-DEA Polymer supported diethyl amine-   soln. solution-   subst. Substituted-   TBTU O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium-   tert. tertiary-   TFA Trifluoroacetic acid-   THF Tetrahydrofuran-   tosyl Toluenesulfonyl-   t_(R) retention time-   Tris Tris-(hydroxymethyl)aminomethane buffer-   UV ultra violet-   Vis visible

Chemistry General Remarks

All solvents and reagents are used as obtained from commercial sourcesunless otherwise indicated.

Temperatures are indicated in degrees Celsius (° C.). Unless otherwiseindicated, the reactions take place at room temperature (r.t.).

In mixtures, relations of parts of solvent or eluent or reagent mixturesin liquid form are given as volume relations (v/v), unless indicatedotherwise.

Analytical HPLC conditions as used in the Examples below:

LC-MS 1

LC-MS-conditions: Analytical. Pump: Waters Acquity Binary SolventManager, MS: Waters SQ Detector, DAD: Acquity UPLC PDA Detector, ELSD:Acquity UPLC ELSD. Column: Acquity UPLC BEH C18 1.7 mm 2.1×50 mm ID fromWaters, thermostated in the Acquity UPLC Column Manager. Eluents: A:H₂O+0.05% formic acid or TFA; B: MeCN+0.05% formic acid or TFA. Method:Gradient: 2% B to 98% B over 2.00 min. Flow: 1.2 mL/min. Detection:UV/Vis and/or ELSD, and MS, t_(R) is given in min

LC-MS 1FA: Eluents: A: H₂O+0.05% formic acid; B: MeCN+0.05% formic acid

LC-MS 1TFA: Eluents: A: H₂O+0.05% TFA; B: MeCN+0.05% TFA

LC-MS 2 to LC-MS 3

HPLC/MS analyses are performed on a Ultimate 3000RS Dionex HPLCinstrument, equipped with a Dionex Ultimate 3000 RS Photodiode ArrayDetector, a Dionex Ultimate 3000RS pump and a Dionex MSQ⁺ massspectrometer.

The LC retention times are obtained using the following elutionconditions:

-   -   LC-MS 2: Analytical HPLC on a Waters X-Bridge C18 column (4.6×30        mm, 2.5 μm, Waters); Linear gradient of water/0.04% TFA (A) and        MeCN (B) from 5% to 95% B over 1.5 min; flow rate 4.5 mL/min,        detection at 215 nm.    -   LC-MS 3: Analytical HPLC on a Zorbax® SB-AQ column (4.6×50 mm,        3.5 μm, Agilent); Linear gradient of water/0.04% TFA (A) and        MeCN (B) from 5% to 95% B over 1.5 min; flow rate 4.5 mL/min,        detection at 215 nm.

Preparative HPLC/MS purifications are performed on a Gilson HPLC system,equipped with a Gilson 215 autosampler, Gilson 333/334 pumps, FinniganAQA MS detector system, and a Dionex UV detector, using a Waters XbridgeC18 or an Waters Atlantis column, with a linear gradient of water/formicacid 0.02% (A) and MeCN (B) (acidic conditions) or water/ammonia 0.02%(A) and MeCN (B) (basic conditions).

Flashmaster purifications are performed using a Büchi system (BüchiFraction Collector C-660, Büchi Pump Manager C-615, Büchi Pump ModuleC-605).

Synthesis of Compounds of Formula (I):

The following examples illustrate the preparation of compounds of theinvention but do not at all limit the scope thereof. First the synthesisof Example compounds of Formula (I) is described, followed by thedescription of the synthesis of intermediates and starting materials.Whenever used in the experimental part, generic Structures 1, 2, 3 etc.refer to the respective Structures described in preceeding generaldescription of the preparation of compounds of Formula (I).

General Method for the Preparation of Compounds of Formula (I):Saponification

To a solution of(±)-{4-chloro-2-[5-(2-fluoro-benzylcarbamoyl)-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4-yl]-phenoxy}-aceticacid ethyl ester (32 mg, 0.06 mmol, 1 eq.) in DMF (1 mL), 1M aq. NaOH(0.50 mL) was added. The mixture was stirred at r.t. for 18 hours. Thesolution was neutralized with formic acid (1 mL) and then purified byprep. HPLC (column: Atlantis, 30×75 mm, 10 um, UV/MS, acidic conditions)and concentrated in vacuo to give the desired acid as a white solid.

Listed in Table 1 below are examples of compounds of Formula (I),prepared according to the above-mentioned method with the correspondingcompound of Structure 1 as starting material.

TABLE 1 t_(R) [min] MS-data Formula LC-MS m/z Example Compound ofFormula (I) MW Method [M + H]⁺ 1 (±)-{4-Chloro-2-[5-(2-fluoro-C22H19N3O4ClFS 0.86 476.2 benzylcarbamoyl)-4,5,6,7- 475.08 LC-MS 1FAtetrahydro-thiazolo[5,4-c]pyridin-4- yl]-phenoxy}-acetic acid 2(±)-{4-Chloro-2-[5-(3-fluoro- C22H19N3O4ClFS 0.86 476.2benzylcarbamoyl)-4,5,6,7- 475.08 LC-MS 1FAtetrahydro-thiazolo[5,4-c]pyridin-4- yl]-phenoxy}-acetic acid 3(±)-{4-Chloro-2-[5-(4-fluoro- C22H19N3O4ClFS 0.86 476.2benzylcarbamoyl)-4,5,6,7- 475.08 LC-MS 1FAtetrahydro-thiazolo[5,4-c]pyridin-4- yl]-phenoxy}-acetic acid 4(±)-[2-(5-Benzylcarbamoyl-4,5,6,7- C22H20N3O4ClS 0.85 458.2tetrahydro-thiazolo[5,4-c]pyridin-4- 457.09 LC-MS 1FAyl)-4-chloro-phenoxy]-acetic acid 5 {4-Chloro-2-[(R)-5-((1R,2R)-2-C24H21N2O4ClS 0.93 469.2 phenyl-cyclopropanecarbonyl)- 468.09 LC-MS 1FA4,5,6,7-tetrahydro-thiazolo[5,4- c]pyridin-4-yl]-phenoxy}-acetic acid 6{4-Chloro-2-[(R)-5-((1S,2S)-2- C24H21N2O4ClS 0.94 469.2phenyl-cyclopropanecarbonyl)- 468.09 LC-MS 1FA4,5,6,7-tetrahydro-thiazolo[5,4- c]pyridin-4-yl]-phenoxy}-acetic acid 7(4-Chloro-2-{(R)-5-[(1R,2R)-2-(3- C24H20N2O4ClFS 0.94 487.2fluoro-phenyl)- 486.08 LC-MS 1FA cyclopropanecarbonyl]-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4- yl}-phenoxy)-acetic acid 8(4-Chloro-2-{(R)-5-[(1R,2R)-2-(4- C24H20N2O4ClFS 0.95 487.2fluoro-phenyl)- 486.08 LC-MS 1FA cyclopropanecarbonyl]-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4- yl}-phenoxy)-acetic acid 9(4-Chloro-2-{(R)-5-[(1S,2S)-2-(4- C24H20N2O4ClFS 0.95 487.2fluoro-phenyl)- 486.08 LC-MS 1FA cyclopropanecarbonyl]-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4- yl}-phenoxy)-acetic acid 10{4-Chloro-2-[(R)-2-methyl-5- C25H23N2O4ClS 0.97 483.2 ((1R,2R)-2-phenyl-482.11 LC-MS 1FA cyclopropanecarbonyl)-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4- yl]-phenoxy}-acetic acid 11{4-Chloro-2-[(S)-2-methyl-5- C25H23N2O4ClS 0.98 483.3 ((1R,2R)-2-phenyl-482.11 LC-MS 1FA cyclopropanecarbonyl)-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4- yl]-phenoxy}-acetic acid 12(±)-4-(2-Carboxymethoxy-5- C23H18N2O5ClF3S 1.16 527.2chloro-phenyl)-2-trifluoromethyl- 526.06 LC-MS 1FA6,7-dihydro-4H-thiazolo[5,4- c]pyridine-5-carboxylic acid benzyl ester13 (±)-4-(2-Carboxymethoxy-5- C25H25N2O5ClS 1.11 501.3chloro-phenyl)-2-isopropyl-6,7- 500.12 LC-MS 1FAdihydro-4H-thiazolo[5,4-c]pyridine- 5-carboxylic acid benzyl ester 14(±)-4-(2-Carboxymethoxy-5- C25H23N2O5ClS 1.08 499.3chloro-phenyl)-2-cyclopropyl-6,7- 498.10 LC-MS 1FAdihydro-4H-thiazolo[5,4-c]pyridine- 5-carboxylic acid benzyl ester 15(±)-4-(2-Carboxymethoxy-5- C23H21N2O5ClS 0.99 473.2chloro-phenyl)-2-methyl-6,7- 472.09 LC-MS 1FAdihydro-4H-thiazolo[5,4-c]pyridine- 5-carboxylic acid benzyl ester 16(±)-4-(2-Carboxymethoxy-5- C24H23N2O5ClS 1.05 487.2chloro-phenyl)-2-ethyl-6,7-dihydro- 486.10 LC-MS 1FA4H-thiazolo[5,4-c]pyridine-5- carboxylic acid benzyl ester 17(±)-2-Amino-4-(2-carboxymethoxy- C22H20N3O5ClS 0.78 474.25-chloro-phenyl)-6,7-dihydro-4H- 473.08 LC-MS thiazolo[5,4-c]pyridine-5-1TFA carboxylic acid benzyl ester 18 (S)-4-(2-Carboxymethoxy-5-C23H21N2O5ClS 0.99 473.2 chloro-phenyl)-2-methyl-6,7- 472.09 LC-MS 1FAdihydro-4H-thiazolo[5,4-c]pyridine- 5-carboxylic acid benzyl ester 19(R)-4-(2-Carboxymethoxy-5- C23H21N2O5ClS 0.99 473.2chloro-phenyl)-2-methyl-6,7- 472.09 LC-MS 1FAdihydro-4H-thiazolo[5,4-c]pyridine- 5-carboxylic acid benzyl ester 20(±)-2-Bromo-4-(2- C22H18N2O5BrClS 1.12 537.0carboxymethoxy-5-chloro-phenyl)- 535.98 LC-MS 1FA6,7-dihydro-4H-thiazolo[5,4- c]pyridine-5-carboxylic acid benzyl ester

Amide Coupling and Subsequent Saponification

Method A: To a solution of 3-(4-fluorophenoxyl)propionic acid (19 mg,0.10 mmol, 1.0 eq.) in DMF (0.25 mL), a solution of TBTU (39 mg, 0.12mmol, 1.2 eq.) in DMF (0.25 mL) and Si-DEA (400 mg, 0.50 mmol, 5 eq.)were added. The resulting mixture was stirred at r.t. for min. Asolution of(±)-[4-chloro-2-(4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4-yl)-phenoxy]-aceticacid ethyl ester hydrochloride (39 mg, 0.10 mmol, 1.0 eq.) in DCM/DMF5:1 (0.6 mL) was added. The mixture was stirred at r.t. for 18 hours.The resulting suspension was filtered, the solids were rinsed with DCM(5 mL), and the filtrate was concentrated in vacuo. The residue wasdissolved in THF (1 mL) and 1M aq. NaOH (1 mL) was added. The mixturewas stirred at r.t. for 30 min. The mixture was neutralized with 2M aq.HCl soln. and concentrated in vacuo. The residue was purified by prep.HPLC (column: Waters X-Bridge, 30×75 mm, 10 urn, UV/MS, acidicconditions) and evaporated to give the desired acid as a white solid.

Listed in Table 2 below are examples of compounds of Formula (I),prepared according to the above-mentioned method with the correspondingamine of Structure 2 (or the corresponding salt) and the correspondingacid as starting materials.

TABLE 2 t_(R) [min] MS-data Formula LC-MS m/z Example Compound ofFormula (I) MW Method [M + H]⁺ 21 (±)-(4-Chloro-2-{5-[3-(4-fluoro-C23H20N2O5ClFS 0.92 491.2 phenoxy)-propionyl]-4,5,6,7- 490.08 LC-MS 1FAtetrahydro-thiazolo[5,4-c]pyridin-4- yl}-phenoxy)-acetic acid 22(±)-{4-Chloro-2-[trans-5-(2-phenyl- C24H21N2O4ClS 0.94 469.2cyclopropanecarbonyl)-4,5,6,7- 468.09 LC-MS 1FAtetrahydro-thiazolo[5,4-c]pyridin-4- yl]-phenoxy}-acetic acid 23(±)-(4-Chloro-2-{trans-5-[2-(2- C25H20N2O4ClF3S 1.01 537.2trifluoromethyl-phenyl)- 536.08 LC-MS 1FA cyclopropanecarbonyl]-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4- yl}-phenoxy)-acetic acid 24(±)-(4-Chloro-2-{trans-5-[2-(2- C24H20N2O4Cl2S 0.98 503.2chloro-phenyl)- 502.05 LC-MS 1FA cyclopropanecarbonyl]-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4- yl}-phenoxy)-acetic acid 25(±)-{4-Chloro-2-[trans-5-(2-o-tolyl- C25H23N2O4ClS 0.98 483.2cyclopropanecarbonyl)-4,5,6,7- 482.11 LC-MS 1FAtetrahydro-thiazolo[5,4-c]pyridin-4- yl]-phenoxy}-acetic acid 26(±)-(4-Chloro-2-{5-[3-(5-methoxy- C26H24N3O5ClS 0.85 526.21H-indol-3-yl)-propionyl]-4,5,6,7- 525.11 LC-MS 1FAtetrahydro-thiazolo[5,4-c]pyridin-4- yl}-phenoxy)-acetic acid 27(±)-(4-Chloro-2-{5-[3-(2-methyl- C26H24N3O4ClS 0.89 510.21H-indol-3-yl)-propionyl]-4,5,6,7- 509.12 LC-MS 1FAtetrahydro-thiazolo[5,4-c]pyridin-4- yl}-phenoxy)-acetic acid 28(±)-(4-Chloro-2-{5-[3-(1-methyl- C26H24N3O4ClS 0.95 510.21H-indol-3-yl)-propionyl]-4,5,6,7- 509.12 LC-MS 1FAtetrahydro-thiazolo[5,4-c]pyridin-4- yl}-phenoxy)-acetic acid 29(±)-{4-Chloro-2-[5-(3-o-tolyl- C24H23N2O4ClS 0.96 471.2propionyl)-4,5,6,7-tetrahydro- 470.11 LC-MS 1FAthiazolo[5,4-c]pyridin-4-yl]- phenoxy}-acetic acid 30(±)-(4-Chloro-2-{5-[4-(2-fluoro- C24H22N2O4ClFS 0.98 489.2phenyl)-butyryl]-4,5,6,7- 488.10 LC-MS 1FAtetrahydro-thiazolo[5,4-c]pyridin-4- yl}-phenoxy)-acetic acid 31(±)-(4-Chloro-2-{5-[2-(2-chloro- C23H20N2O5Cl2S 0.94 507.2benzyloxy)-acetyl]-4,5,6,7- 506.05 LC-MS 1FAtetrahydro-thiazolo[5,4-c]pyridin-4- yl}-phenoxy)-acetic acid 32(±)-(4-Chloro-2-{5-[2-(2,6- C23H22N3O5ClS 0.57 488.2dimethyl-pyridin-3-yloxy)-acetyl]- 487.10 LC-MS 1FA4,5,6,7-tetrahydro-thiazolo[5,4- c]pyridin-4-yl}-phenoxy)-acetic acid 33(±)-{4-Chloro-2-[5-(3-indazol-1-yl- C24H21N4O4ClS 0.85 497.2propionyl)-4,5,6,7-tetrahydro- 496.10 LC-MS 1FAthiazolo[5,4-c]pyridin-4-yl]- phenoxy}-acetic acid 34(±)-{4-Chloro-2-[5-(2-phenoxy- C22H19N2O5ClS 0.86 459.2acetyl)-4,5,6,7-tetrahydro- 458.07 LC-MS 1FAthiazolo[5,4-c]pyridin-4-yl]- phenoxy}-acetic acid 35(±)-{4-Chloro-2-[5-((S)-3-phenyl- C24H23N2O4ClS 0.94 471.2butyryl)-4,5,6,7-tetrahydro- 470.11 LC-MS 1FAthiazolo[5,4-c]pyridin-4-yl]- phenoxy}-acetic acid 36(±)-{4-Chloro-2-[5-(indane-2- C24H21N2O4ClS 0.96 469.2carbonyl)-4,5,6,7-tetrahydro- 468.09 LC-MS 1FAthiazolo[5,4-c]pyridin-4-yl]- phenoxy}-acetic acid 37(±)-(4-Chloro-2-{5-[2-(1-phenyl- C25H23N2O4ClS 0.95 483.3cyclopropyl)-acetyl]-4,5,6,7- 482.11 LC-MS 1FAtetrahydro-thiazolo[5,4-c]pyridin-4- yl}-phenoxy)-acetic acid 38(±)-{4-Chloro-2-[5-((R)-3-phenyl- C24H23N2O4ClS 0.93 471.2butyryl)-4,5,6,7-tetrahydro- 470.11 LC-MS 1FAthiazolo[5,4-c]pyridin-4-yl]- phenoxy}-acetic acid 39(±)-{4-Chloro-2-[5-((±)-2- C25H23N2O5ClS 0.93 499.3isochroman-1-yl-acetyl)-4,5,6,7- 498.10 LC-MS 1FAtetrahydro-thiazolo[5,4-c]pyridin-4- yl]-phenoxy}-acetic acid 40(±)-{4-Chloro-2-[5-(3,3-dimethyl- C20H23N2O4ClS 0.91 423.3butyryl)-4,5,6,7-tetrahydro- 422.11 LC-MS 1FAthiazolo[5,4-c]pyridin-4-yl]- phenoxy}-acetic acid 41(±)-{4-Chloro-2-[5-(2-cyclopropyl- C19H19N2O4ClS 0.80 407.2acetyl)-4,5,6,7-tetrahydro- 406.08 LC-MS 1FAthiazolo[5,4-c]pyridin-4-yl]- phenoxy}-acetic acid 42(±)-(4-Chloro-2-{5-[3-(3,5- C22H22N3O5ClS 0.78 476.2dimethyl-isoxazol-4-yl)-propionyl]- 475.10 LC-MS 1FA4,5,6,7-tetrahydro-thiazolo[5,4- c]pyridin-4-yl}-phenoxy)-acetic acid 43(±)-[4-Chloro-2-(5- C18H17N2O4ClS 0.75 393.2cyclopropanecarbonyl-4,5,6,7- 392.06 LC-MS 1FAtetrahydro-thiazolo[5,4-c]pyridin-4- yl)-phenoxy]-acetic acid 44(±)-{4-Chloro-2-[5-(2-1H-indazol-3- C23H19N4O4ClS 0.78 483.2yl-acetyl)-4,5,6,7-tetrahydro- 482.08 LC-MS 1FAthiazolo[5,4-c]pyridin-4-yl]- phenoxy}-acetic acid 45(±)-(4-Chloro-2-{5-[(E)-(3-phenyl- C23H19N2O4ClS 0.92 455.2acryloyl)]-4,5,6,7-tetrahydro- 454.08 LC-MS 1FAthiazolo[5,4-c]pyridin-4-yl}- phenoxy)-acetic acid 46(±)-{4-Chloro-2-[5-(2-indan-2-yl- C25H23N2O4ClS 0.99 483.3acetyl)-4,5,6,7-tetrahydro- 482.11 LC-MS 1FAthiazolo[5,4-c]pyridin-4-yl]- phenoxy}-acetic acid 47(±)-{4-Chloro-2-[(±)-5-(2,2- C20H21N2O4ClS 0.86 421.2dimethyl-cyclopropanecarbonyl)- 420.09 LC-MS 1FA4,5,6,7-tetrahydro-thiazolo[5,4- c]pyridin-4-yl]-phenoxy}-acetic acid 48(±)-{4-Chloro-2-[5-(2-cyclohexyl- C22H25N2O4ClS 0.99 449.3acetyl)-4,5,6,7-tetrahydro- 448.12 LC-MS 1FAthiazolo[5,4-c]pyridin-4-yl]- phenoxy}-acetic acid 49(±)-{4-Chloro-2-[5-(2-naphthalen- C26H21N2O4ClS 0.97 493.32-yl-acetyl)-4,5,6,7-tetrahydro- 492.09 LC-MS 1FAthiazolo[5,4-c]pyridin-4-yl]- phenoxy}-acetic acid 50(±)-{4-Chloro-2-[5-(2-naphthalen- C26H21N2O4ClS 0.97 493.21-yl-acetyl)-4,5,6,7-tetrahydro- 492.09 LC-MS 1FAthiazolo[5,4-c]pyridin-4-yl]- phenoxy}-acetic acid 51(±)-(4-Chloro-2-{5-[4-(4-fluoro- C24H22N2O4ClFS 0.98 489.2phenyl)-butyryl]-4,5,6,7- 488.10 LC-MS 1FAtetrahydro-thiazolo[5,4-c]pyridin-4- yl}-phenoxy)-acetic acid 52(±)-{4-Chloro-2-[5-(3-2,3-dihydro- C25H24N3O4ClS 0.93 498.3indol-1-yl-propionyl)-4,5,6,7- 497.12 LC-MS 1FAtetrahydro-thiazolo[5,4-c]pyridin-4- yl]-phenoxy}-acetic acid 53(±)-{4-Chloro-2-[5-(3-3,4-dihydro- C26H26N3O4ClS 0.99 512.32H-quinolin-1-yl-propionyl) 511.13 LC-MS 1FA4,5,6,7-tetrahydro-thiazolo[5,4- c]pyridin-4-yl]-phenoxy}-acetic acid

Method B: To a solution of 4-methoxycinnamic acid (19 mg, 0.11 mmol, 1.2eq.) in DCM (2 mL), DIPEA (62 μL, 0.36 mmol, 4.0 eq.) and TBTU (35 mg,0.11 mmol, 1.2 eq.) were added in sequence. The resulting solution wasstirred at r.t. for 30 min. Then(±)-[4-chloro-2-(4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4-yl)-phenoxy]-aceticacid ethyl ester hydrochloride (35 mg, 0.09 mmol, 1.0 eq.) was added andthe resulting mixture was stirred at r.t. for 18 hours. The mixture wasconcentrated in vacuo. The residue was dissolved in DMF (0.8 mL). 1M aq.NaOH soln. (1 mL) was added. The mixture was stirred at r.t. for 3hours. The solution was carefully neutralized with formic acid (0.5 mL),and purified by prep. HPLC (column: Atlantis, 30×75 mm, 10 um, UV/MS,acidic conditions) and concentrated in vacuo to give the desired acid asa white solid.

Listed in Table 3 below are examples of compounds of Formula (I),prepared according to the above-mentioned method with the correspondingamine of Structure 2 (or the corresponding salt) and the correspondingacid as starting materials.

TABLE 3 t_(R) [min] MS-data Formula LC-MS m/z Example Compound ofFormula (I) MW Method [M + H]⁺ 54 (±)-(4-Chloro-2-{5-[(E)-3-(4-C24H21N2O5ClS 0.93 485.2 methoxy-phenyl)-acryloyl]-4,5,6,7- 484.09 LC-MS1FA tetrahydro-thiazolo[5,4-c]pyridin-4- yl}-phenoxy)-acetic acid 55(±)-(4-Chloro-2-{5-[(E)-3-(4-fluoro- C23H18N2O4ClFS 0.94 473.2phenyl)-acryloyl]-4,5,6,7- 472.07 LC-MS 1FAtetrahydro-thiazolo[5,4-c]pyridin-4- yl}-phenoxy)-acetic acid 56(±)-{4-Chloro-2-[5-((E)-3-p-tolyl- C24H21N2O4ClS 0.99 469.2acryloyl)-4,5,6,7-tetrahydro- 468.09 LC-MS 1FAthiazolo[5,4-c]pyridin-4-yl]- phenoxy}-acetic acid 57(±)-(4-Chloro-2-{5-[(E)-3-(2,4- C23H17N2O4ClF2S 0.96 491.2difluoro-phenyl)-acryloyl]-4,5,6,7- 490.06 LC-MS 1FAtetrahydro-thiazolo[5,4-c]pyridin-4- yl}-phenoxy)-acetic acid

Carbamate Formation and Subsequent Saponification

Method A: To a solution of(R)-4-(5-chloro-2-ethoxycarbonylmethoxy-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylicacid 4-nitro-phenyl ester (38 mg, 0.07 mmol, 1 eq.) and2,5-difluorobenzalcohol (32 mg, 0.22 mmol, 3 eq.) in THF (2 mL),potassium tert-butoxide (26 mg, 0.22 mmol, 3 eq.) was added. The mixturewas stirred at r.t. for 18 hours. The solvent was removed in vacuo. Theresidue was dissolved in MeCN/H₂O 1:1 (1 mL), formic acid (0.2 mL) wasadded followed by DMF (0.6 mL). The resulting solution was purified byprep. HPLC (column: Atlantis, 18×50 mm, 10 um, UV/MS, acidic conditions)and concentrated in vacuo to give the desired acid as a white solid.

Listed in Table 4 below are examples of compounds of Formula (I),prepared according to the above-mentioned method with the corresponding4-nitrophenol carbamate 5 and the corresponding alcohol as startingmaterials.

TABLE 4 t_(R) [min] MS-data Formula LC-MS m/z Example Compound ofFormula (I) MW Method [M + H]⁺ 58 (R)-4-(2-Carboxymethoxy-5-C22H17N2O5ClF2S 0.97 495.2 chloro-phenyl)-6,7-dihydro-4H- 494.05 LC-MS1FA thiazolo[5,4-c]pyridine-5- carboxylic acid 2,5-difluoro-benzyl ester59 (R)-4-(2-Carboxymethoxy-5- C22H17N2O5ClF2S 0.98 495.2chloro-phenyl)-6,7-dihydro-4H- 494.05 LC-MS 1FAthiazolo[5,4-c]pyridine-5- carboxylic acid 2,4-difluoro-benzyl ester 60(R)-4-(2-Carboxymethoxy-5- C21H25N2O5ClS 1.05 453.3chloro-phenyl)-6,7-dihydro-4H- 452.12 LC-MS 1FAthiazolo[5,4-c]pyridine-5- carboxylic acid 2,2-dimethyl-butyl ester 61(R)-4-(2-Carboxymethoxy-5- C22H18N2O5ClFS 0.97 477.2chloro-phenyl)-6,7-dihydro-4H- 476.06 LC-MS 1FAthiazolo[5,4-c]pyridine-5- carboxylic acid 4-fluoro-benzyl ester 62(R)-4-(2-Carboxymethoxy-5- C21H25N2O6ClS 0.91 469.2chloro-phenyl)-6,7-dihydro-4H- 468.11 LC-MS 1FAthiazolo[5,4-c]pyridine-5- carboxylic acid 3-methoxy-3- methyl-butylester 63 (R)-4-(2-Carboxymethoxy-5- C24H32N2O5ClS 1.06 487.2chloro-phenyl)-6,7-dihydro-4H- 486.10 LC-MS 1FAthiazolo[5,4-c]pyridine-5- carboxylic acid 2,4-dimethyl- benzyl ester 64(R)-4-(2-Carboxymethoxy-5- C22H17N2O5Cl2FS 1.02 511.1chloro-phenyl)-6,7-dihydro-4H- 510.02 LC-MS 1FAthiazolo[5,4-c]pyridine-5- carboxylic acid 2-chloro-5-fluoro- benzylester 65 (R)-4-(2-Carboxymethoxy-5- C21H25N2O5ClS 1.07 453.2chloro-phenyl)-6,7-dihydro-4H- 452.12 LC-MS 1FAthiazolo[5,4-c]pyridine-5- carboxylic acid 3,3-dimethyl-butyl ester 66(R)-4-(2-Carboxymethoxy-5- C22H25N2O5ClS 1.09 465.2chloro-phenyl)-6,7-dihydro-4H- 464.12 LC-MS 1FAthiazolo[5,4-c]pyridine-5- carboxylic acid cyclohexylmethyl ester 67(R)-4-(2-Carboxymethoxy-5- C20H23N2O5ClS 1.02 439.2chloro-phenyl)-6,7-dihydro-4H- 438.10 LC-MS 1FAthiazolo[5,4-c]pyridine-5- carboxylic acid 3-methyl-butyl ester 68(R)-4-(2-Carboxymethoxy-5- C22H17N2O5Cl2FS 1.02 511.2chloro-phenyl)-6,7-dihydro-4H- 510.02 LC-MS 1FAthiazolo[5,4-c]pyridine-5- carboxylic acid 5-chloro-2-fluoro- benzylester 69 (R)-4-(2-Carboxymethoxy-5- C20H21N2O5ClS 0.99 437.2chloro-phenyl)-6,7-dihydro-4H- 436.09 LC-MS 1FAthiazolo[5,4-c]pyridine-5- carboxylic acid cyclobutylmethyl ester 70(R)-4-(2-Carboxymethoxy-5- C20H23N2O5ClS 1.01 439.2chloro-phenyl)-6,7-dihydro-4H- 438.10 LC-MS 1FAthiazolo[5,4-c]pyridine-5- carboxylic acid (±)-2-methyl-butyl ester 71(R)-4-(2-Carboxymethoxy-5- C22H17N2O5ClF2S 0.98 495.2chloro-phenyl)-6,7-dihydro-4H- 494.05 LC-MS 1FAthiazolo[5,4-c]pyridine-5- carboxylic acid 2,3-difluoro-benzyl ester 72(R)-4-(2-Carboxymethoxy-5- C24H23N2O5ClS 1.05 487.2chloro-phenyl)-6,7-dihydro-4H- 486.10 LC-MS 1FAthiazolo[5,4-c]pyridine-5- carboxylic acid 2,3-dimethyl- benzyl ester 73(R)-4-(2-Carboxymethoxy-5- C22H17N2O5ClF2S 0.96 495.2chloro-phenyl)-6,7-dihydro-4H- 494.05 LC-MS 1FAthiazolo[5,4-c]pyridine-5- carboxylic acid 2,6-difluoro-benzyl ester 74(R)-4-(2-Carboxymethoxy-5- C18H18N2O5ClFS 0.83 429.2chloro-phenyl)-6,7-dihydro-4H- 428.06 LC-MS 1FAthiazolo[5,4-c]pyridine-5- carboxylic acid 3-fluoro-propyl ester 75(R)-4-(2-Carboxymethoxy-5- C22H18N2O5ClFS 0.96 477.2chloro-phenyl)-6,7-dihydro-4H- 476.06 LC-MS 1FAthiazolo[5,4-c]pyridine-5- carboxylic acid 2-fluoro-benzyl ester 76(R)-4-(2-Carboxymethoxy-5- C22H18N2O5ClFS 0.97 477.2chloro-phenyl)-6,7-dihydro-4H- 476.06 LC-MS 1FAthiazolo[5,4-c]pyridine-5- carboxylic acid 3-fluoro-benzyl ester 77(±)-4-(2-Carboxymethoxy-5- C23H20N2O5ClFS 1.00 491.2chloro-phenyl)-6,7-dihydro-4H- 490.08 LC-MS 1FAthiazolo[5,4-c]pyridine-5- carboxylic acid 2-(3-fluoro- phenyl)-ethylester 78 (±)-4-(2-Carboxymethoxy-5- C22H18N2O5ClFS 0.97 477.2chloro-phenyl)-6,7-dihydro-4H- 476.06 LC-MS 1FAthiazolo[5,4-c]pyridine-5- carboxylic acid 3-fluoro-benzyl ester 79(±)-4-(2-Carboxymethoxy-5- C22H18N2O5ClFS 0.96 477.2chloro-phenyl)-6,7-dihydro-4H- 476.06 LC-MS 1FAthiazolo[5,4-c]pyridine-5- carboxylic acid 2-fluoro-benzyl ester 80(±)-4-(2-Carboxymethoxy-5- C22H18N2O5ClFS 0.97 477.2chloro-phenyl)-6,7-dihydro-4H- 476.06 LC-MS 1FAthiazolo[5,4-c]pyridine-5- carboxylic acid 4-fluoro-benzyl ester 81(±)-4-(2-Carboxymethoxy-5- C22H17N2O5Cl3S 1.07 527.1chloro-phenyl)-6,7-dihydro-4H- 525.99 LC-MS 1FAthiazolo[5,4-c]pyridine-5- carboxylic acid 2,3-dichloro-benzyl ester 82(±)-4-(2-Carboxymethoxy-5- C22H17N2O5ClF2S 0.98 495.2chloro-phenyl)-6,7-dihydro-4H- 494.05 LC-MS 1FAthiazolo[5,4-c]pyridine-5- carboxylic acid 2,3-difluoro-benzyl ester 83(±)-4-(2-Carboxymethoxy-5- C22H17N2O5ClF2S 0.98 495.2chloro-phenyl)-6,7-dihydro-4H- 494.05 LC-MS 1FAthiazolo[5,4-c]pyridine-5- carboxylic acid 2,4-difluoro-benzyl ester 84(±)-4-(2-Carboxymethoxy-5- C22H18N2O5Cl2S 1.01 493.2chloro-phenyl)-6,7-dihydro-4H- 492.03 LC-MS 1FAthiazolo[5,4-c]pyridine-5- carboxylic acid 2-chloro-benzyl ester 85(±)-4-(2-Carboxymethoxy-5- C22H18N2O5Cl2S 1.02 493.1chloro-phenyl)-6,7-dihydro-4H- 492.03 LC-MS 1FAthiazolo[5,4-c]pyridine-5- carboxylic acid 3-chloro-benzyl ester 86(±)-4-(2-Carboxymethoxy-5- C22H18N2O5Cl2S 1.03 493.1chloro-phenyl)-6,7-dihydro-4H- 492.03 LC-MS 1FAthiazolo[5,4-c]pyridine-5- carboxylic acid 4-chloro-benzyl ester 87(±)-4-(2-Carboxymethoxy-5- C22H17N2O5Cl3S 1.04 527.1chloro-phenyl)-6,7-dihydro-4H- 525.99 LC-MS 1FAthiazolo[5,4-c]pyridine-5- carboxylic acid 2,6-dichloro-benzyl ester 88(±)-4-(2-Carboxymethoxy-5- C23H21N2O5ClS 0.99 473.2chloro-phenyl)-6,7-dihydro-4H- 472.09 LC-MS 1FAthiazolo[5,4-c]pyridine-5- carboxylic acid phenethyl ester 89(±)-4-(2-Carboxymethoxy-5- C22H17N2O5ClF2S 0.96 495.2chloro-phenyl)-6,7-dihydro-4H- 494.05 LC-MS 1FAthiazolo[5,4-c]pyridine-5- carboxylic acid 2,6-difluoro-benzyl ester 90(±)-4-(2-Carboxymethoxy-5- C23H19N4O5ClS 0.90 499.2chloro-phenyl)-6,7-dihydro-4H- 498.08 LC-MS 1FAthiazolo[5,4-c]pyridine-5- carboxylic acid indazol-1-ylmethyl ester 91(±)-4-(2-Carboxymethoxy-5- C23H25N4O5ClS 0.82 505.3chloro-phenyl)-6,7-dihydro-4H- 504.12 LC-MS 1FAthiazolo[5,4-c]pyridine-5- carboxylic acid 2-(2-ethyl-5-methyl-2H-pyrazol-3-yl)-ethyl ester 92 (±)-4-(2-Carboxymethoxy-5-C22H17N2O5Cl2FS 1.02 511.1 chloro-phenyl)-6,7-dihydro-4H- 510.02 LC-MS1FA thiazolo[5,4-c]pyridine-5- carboxylic acid 2-chloro-5-fluoro- benzylester 93 (±)-4-(2-Carboxymethoxy-5- C22H17N2O5ClF2S 0.97 495.2chloro-phenyl)-6,7-dihydro-4H- 494.05 LC-MS 1FAthiazolo[5,4-c]pyridine-5- carboxylic acid 2,5-difluoro-benzyl ester 94(±)-4-(2-Carboxymethoxy-5- C22H17N2O5Cl3S 1.10 527.1chloro-phenyl)-6,7-dihydro-4H- 525.99 LC-MS 1FAthiazolo[5,4-c]pyridine-5- carboxylic acid 2,4-dichloro-benzyl ester 95(±)-4-(2-Carboxymethoxy-5- C20H17N4O5ClS 0.74 461.2chloro-phenyl)-6,7-dihydro-4H- 460.06 LC-MS 1FAthiazolo[5,4-c]pyridine-5- carboxylic acid pyrazin-2-ylmethyl ester 96(±)-4-(2-Carboxymethoxy-5- C22H25N2O5ClS 1.09 465.2chloro-phenyl)-6,7-dihydro-4H- 464.12 LC-MS 1FAthiazolo[5,4-c]pyridine-5- carboxylic acid cyclohexylmethyl ester 97(±)-4-(2-Carboxymethoxy-5- C23H18N3O6ClS 0.91 500.2chloro-phenyl)-6,7-dihydro-4H- 499.06 LC-MS 1FAthiazolo[5,4-c]pyridine-5- carboxylic acid benzooxazol-2- ylmethyl ester98 (±)-4-(2-Carboxymethoxy-5- C19H21N2O5ClS 0.96 425.2chloro-phenyl)-6,7-dihydro-4H- 424.09 LC-MS 1FAthiazolo[5,4-c]pyridine-5- carboxylic acid isobutyl ester 99(±)-4-(2-Carboxymethoxy-5- C19H21N2O5ClS 0.97 425.2chloro-phenyl)-6,7-dihydro-4H- 424.09 LC-MS 1FAthiazolo[5,4-c]pyridine-5- carboxylic acid butyl ester 100(±)-4-(2-Carboxymethoxy-5- C24H23N2O5ClS 1.06 487.2chloro-phenyl)-6,7-dihydro-4H- 486.10 LC-MS 1FAthiazolo[5,4-c]pyridine-5- carboxylic acid 2,4-dimethyl- benzyl ester101 (±)-4-(2-Carboxymethoxy-5- C24H23N2O5ClS 1.05 487.2chloro-phenyl)-6,7-dihydro-4H- 486.10 LC-MS 1FAthiazolo[5,4-c]pyridine-5- carboxylic acid 2,3-dimethyl- benzyl ester102 (±)-4-(2-Carboxymethoxy-5- C22H17N2O5Cl2FS 1.02 511.2chloro-phenyl)-6,7-dihydro-4H- 510.02 LC-MS 1FAthiazolo[5,4-c]pyridine-5- carboxylic acid 5-chloro-2-fluoro- benzylester

Method B: To a solution of((R)-4-chloro-2-(4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4-yl)-phenoxy)-aceticacid ethyl ester hydrochloride (50 mg, 0.13 mmol, 1.0 eq.) and DIPEA (88μL, 0.51 mmol, 4.0 eq.) in DCM (5 mL), benzyl chloroformate (20 μL, 0.14mmol, 1.1 eq.) was added. The resulting solution was stirred at r.t. for18 hours. The reaction mixture was concentrated in vacuo. The residuewas dissolved in DMF (1 mL) and 1M aq. NaOH soln. (0.50 mL) was added.The mixture was stirred at r.t. for 2 hours. The solution wasneutralized with formic acid (0.50 mL) and then purified by prep. HPLC(column: Atlantis, 18×50 mm, 10 um, UV/MS, acidic conditions) andconcentrated in vacuo to give the desired acid as a white solid.

Listed in Table 5 below are examples of compounds of Formula (I),prepared according to the above-mentioned method with the correspondingcompound of Structure 2 (or the corresponding salt) as startingmaterial.

TABLE 5 t_(R) [min] MS-data Formula LC-MS m/z Example Compound ofFormula (I) MW Method [M + H]⁺ 103 (R)-4-(2-Carboxymethoxy-5-C22H19N2O5ClS 0.96 459.2 chloro-phenyl)-6,7-dihydro-4H- 458.07 LC-MS 1FAthiazolo[5,4-c]pyridine-5- carboxylic acid benzyl ester 104(S)-4-(2-Carboxymethoxy-5- C22H19N2O5ClS 0.96 459.2chloro-phenyl)-6,7-dihydro-4H- 458.07 LC-MS 1FAthiazolo[5,4-c]pyridine-5- carboxylic acid benzyl ester 105(±)-4-(2-Carboxymethoxy-5- C22H19N2O5ClS 0.96 459.2chloro-phenyl)-6,7-dihydro-4H- 458.07 LC-MS 1FAthiazolo[5,4-c]pyridine-5- carboxylic acid benzyl ester 106(±)-4-(2-Carboxymethoxy-5- C23H19N3O5S 0.82 450.2cyano-phenyl)-6,7-dihydro-4H- 449.11 LC-MS 1FAthiazolo[5,4-c]pyridine-5- carboxylic acid benzyl ester

Urea Formation and Subsequent Saponification

To a solution of(±)-[4-chloro-2-(4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4-yl)-phenoxy]-aceticacid ethyl ester hydrochloride (50 mg, 0.13 mmol, 1.00 eq.) and NEt₃ (54μL, 0.39 mmol, 3.00 eq.) in MeCN (1 mL), phenethyl isocyanate (20 mg,0.14 mmol, 1.05 eq.) in MeCN (1 mL) was added. The mixture was stirredat r.t. for 18 hours. 1M aq. NaOH (0.5 mL) was added. The mixture wasstirred at r.t. for 18 hours. The solution was neutralized with formicacid and purified by prep. HPLC (column: Atlantis, 30×75 mm, 10 um,UV/MS, acidic conditions) and concentrated in vacuo to give the desiredacid as a white solid.

Listed in Table 6 below are examples of compounds of Formula (I),prepared according to the above-mentioned method with the correspondingamine of Structure 2 (or the corresponding salt) and the correspondingisocyanate as starting materials.

TABLE 6 t_(R) [min] MS-data Formula LC-MS m/z Example Compound ofFormula (I) MW Method [M + H]⁺ 107 (±)-[4-Chloro-2-(5- C23H22N3O4ClS0.88 472.2 phenethylcarbamoyl-4,5,6,7- 471.10 LC-MS 1FAtetrahydro-thiazolo[5,4-c]pyridin-4- yl)-phenoxy]-acetic acid 108(±)-{4-Chloro-2-[5-(2-chloro- C22H19N3O4Cl2S 0.89 492.2benzylcarbamoyl)-4,5,6,7- 491.05 LC-MS 1FAtetrahydro-thiazolo[5,4-c]pyridin-4- yl]-phenoxy}-acetic acid 109(±)-{4-Chloro-2-[5-(2-methoxy- C23H22N3O5ClS 0.86 488.2benzylcarbamoyl)-4,5,6,7- 487.10 LC-MS 1FAtetrahydro-thiazolo[5,4-c]pyridin-4- yl]-phenoxy}-acetic acid

Example 110(±)-{4-Chloro-2-[5-(2-methoxy-benzylthiocarbamoyl)-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4-yl]-phenoxy}-aceticacid (C23H22N3O4ClS2, MW=503.07)

To a solution of(±)-[4-chloro-2-(4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4-yl)-phenoxy]-aceticacid ethyl ester hydrochloride (50 mg, 0.13 mmol, 1.00 eq.) and NEt₃ (54μL, 0.39 mmol, 3.00 eq.) in MeCN (1 mL), 2-methoxybenzyl isothiocyanate(24 mg, 0.14 mmol, 1.05 eq.) in MeCN (1 mL) was added. The mixture wasstirred at r.t. for 18 hours. 1M aq. NaOH (0.5 mL) was added. Themixture was stirred at r.t. for 18 hours. The solution was neutralizedwith formic acid, purified by prep. HPLC (column: Atlantis, 30×75 mm, 10um, UV/MS, acidic conditions), and concentrated in vacuo to give thedesired acid as a white solid.

LC-MS 1FA: t_(R)=0.95 min; [M+H]⁺=504.2

Example 111(±)-4-(2-Carboxymethoxy-5-chloro-phenyl)-2-propyl-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylicacid benzyl ester (C25H25N2O5ClS, MW=500.12)

To a solution under N₂ of(±)-2-bromo-4-(5-chloro-2-ethoxycarbonylmethoxy-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylicacid benzyl ester (50 mg, 0.09 mmol, 1.00 eq.) and 0.5M propylzincbromide in THF (0.36 mL, 0.18 mmol, 2.00 eq.) in THF (10 mL),tetrakis(triphenylphosphine) palladium (0) (5.1 mg, 4 μmol, 0.05 eq) wasadded. The mixture was stirred at 50° C. for 18 hours. The mixture wasallowed to cool to r.t. and concentrated in vacuo. The residue was takenup in DMF, filtered, and purified by prep. HPLC (column: Atlantis, 30×75mm, 10 um, UV/MS, acidic conditions) and concentrated in vacuo. Theresulting ester was dissolved in DMF (0.5 mL), 1M aq. NaOH soln. (0.5mL) was added. The resulting solution was stirred at r.t. for 18 hours.The solution was neutralized with formic acid (1 mL), filtered, and thenpurified by prep. HPLC (column: Atlantis, 30×75 mm, 10 um, UV/MS, acidicconditions) and concentrated in vacuo to give the desired acid as awhite solid.

LC-MS 1 FA: t_(R)=1.11 min; [M+H]⁺=501.2

Example 112(±)-4-(2-Carboxymethoxy-5-chloro-phenyl)-2-phenyl-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylicacid benzyl ester (C28H23N2O5ClS, MW=534.10)

To a mixture under N₂ of(±)-2-bromo-4-(5-chloro-2-ethoxycarbonylmethoxy-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylicacid benzyl ester (63 mg, 0.12 mmol, 1.00 eq.), phenylboronic acid (15mg, 0.12 mmol, 1.00 eq.) and sodium carbonate (50 mg, 0.47 mmol, 4.00eq.) in toluene/MeOH/Water 20:4:1 (4 mL), tetrakis(triphenylphosphine)palladium (0) (6.8 mg, 6 μmol, 0.05 eq.) was added and the mixture wasstirred at 100° C. for 18 hours. The mixture was allowed to cool to r.t.and concentrated in vacuo. The residue was partitioned between AcOEt (25mL) and water (25 mL). The layers were separated. The org. phase waswashed with sat. aq. NaCl soln. (1×12 mL), dried over MgSO₄ and filteredthrough Celite. The filtrate was concentrated in vacuo. The residue wasdissolved in DMF (0.5 mL), 1M aq. NaOH soln. (0.5 mL) was added. Theresulting solution was stirred at r.t. for 18 hours. The solution wasneutralized with formic acid (1 mL), filtered, and then purified byprep. HPLC (column: Atlantis, 30×75 mm, 10 um, UV/MS, acidic conditions)and concentrated in vacuo to give the desired acid as a white solid.

LC-MS 1FA: t_(R)=1.20 min; [M+H]⁺=535.2

Sulfonamide Formation and Saponification

To a solution of(±)-2-amino-4-(5-chloro-2-ethoxycarbonylmethoxy-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylicacid benzyl ester (50 mg, 0.10 mmol, 1.00 eq.) and NEt₃ (69 μL, 0.50mmol, 5.00 eq.) in THF (2 mL), methanesulfonyl chloride (7.7 μL, 0.10mmol, 1.00 eq.) and DMAP (3.0 mg, 0.025 mmol, 0.25 eq.) were added insequence. The resulting solution was stirred at 80° C. for 18 hours. Themixture was allowed to cool to r.t. and concentrated in vacuo. Theresidue was taken up in DMF, filtered, and purified by prep. HPLC(column Atlantis, 30×75 mm, 10 um, UV/MS, acidic conditions) andconcentrated in vacuo. The resulting ester was dissolved in DMF (0.5 mL)and 1M aq. NaOH soln. (0.5 mL) was added. The resulting solution wasstirred at r.t. for 18 hours. The solution was neutralized with formicacid (1 mL), filtered, and purified by prep. HPLC (column: Atlantis,30×75 mm, 10 um, UV/MS, acidic conditions) and concentrated in vacuo togive the desired acid as a white solid.

Listed in Table 7 below are examples of compounds of Formula (I),prepared according to the above-mentioned method with the correspondingsulfonyl chloride as starting material.

TABLE 7 t_(R) [min] MS-data Formula LC-MS m/z Example Compound ofFormula (I) MW Method [M + H]⁺ 113 (±)-4-(2-Carboxymethoxy-5-C23H22N3O7ClS2 0.87 552.2 chloro-phenyl)-2- 551.06 LC-MS 1FAmethanesulfonylamino-6,7- dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic acid benzyl ester 114 (±)-4-(2-Carboxymethoxy-5-C25H24N3O7ClS2 0.91 578.2 chloro-phenyl)-2- 577.07 LC-MS 1FAcyclopropanesulfonylamino-6,7- dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic acid benzyl ester

Acylation and Saponification

To an ice-cooled solution of(±)-2-amino-4-(5-chloro-2-ethoxycarbonylmethoxy-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylicacid benzyl ester (50 mg, 0.10 mmol, 1 eq.) and NEt₃ (69 μL, 0.50 mmol,5 eq.) in DCM (1 mL), cyclopropanecarbonylchloride (19 μL, 0.20 mmol, 2eq.) was added dropwise. Upon completion of the addition, the coolingbath was removed and the solution was stirred at r.t. for 3 hours. Thesolvent was removed in vacuo. The residue was dissolved in DMF (0.5 mL),1M aq. NaOH soln. (0.5 mL) was added. The resulting solution was stirredat r.t. for 18 hours. The solution was neutralized with formic acid (1mL), filtered, purified by prep. HPLC (column: Atlantis, 30×75 mm, 10um, UV/MS, acidic conditions), and concentrated in vacuo to give thedesired acid as a white solid.

Listed in Table 8 below are examples of compounds of Formula (I),prepared according to the above-mentioned method with the correspondingacyl chloride as starting material.

TABLE 8 t_(R) [min] MS-data Formula LC-MS m/z Example Compound ofFormula (I) MW Method [M + H]⁺ 115 (±)-4-(2-Carboxymethoxy-5-C26H24N3O6ClS 0.98 542.3 chloro-phenyl)-2- 541.11 LC-MS 1FA(cyclopropanecarbonyl-amino)- 6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic acid benzyl ester 116 (±)-2-Acetylamino-4-(2-C24H22N3O6ClS 0.91 516.2 carboxymethoxy-5-chloro-phenyl)- 515.09 LC-MS1FA 6,7-dihydro-4H-thiazolo[5,4- c]pyridine-5-carboxylic acid benzylester

Example 117(±)-4-(2-Carboxymethoxy-5-chloro-phenyl)-2-dimethylamino-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylicacid benzyl ester (C24H24N3O5ClS, MW=501.11)

A solution of(±)-2-bromo-4-(2-carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylicacid benzyl ester (21 mg, 0.04 mmol, 1.0 eq.) in 2M dimethylamine in THF(0.5 mL) was heated at 80° C. for 18 hours. The reaction mixture wasallowed to cool to r.t. and concentrated in vacuo. The residue was takenup in DMF, filtered, and purified by prep. HPLC (column: Atlantis, 30×75mm, 10 um, UV/MS, acidic conditions) and concentrated in vacuo to givethe title compound as a white solid.

LC-MS 1TFA: t_(R)=0.81 min; [M+H]⁺=502.2

Example 118(±)-4-(2-Carboxymethoxy-5-fluoro-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylicacid benzyl ester (C22H19N2O5FS, MW=442.10)

Trifluoroacetic acid (8.2 mL) was added to a solution of(±)-4-(2-ethoxycarbonylmethoxy-5-fluoro-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylicacid tert-butyl ester (237 mg, 0.52 mmol, 1.0 eq.) in DCM (12 mL). Theresulting mixture was stirred at r.t. for 5 hours. The solvent wasremoved in vacuo. To an-ice cooled suspension of the residue andtriethylamine (0.11 mL, 0.79 mmol, 1.5 eq.) in DCM (5 mL), benzylchloroformate (79 μL, 0.52 mmol, 1.0 eq.) was added dropwise. Uponcompletion of the addition, the cooling bath was removed and thesuspension was stirred at r.t. for 18 hours. Triethylamine (0.11 mL,0.79 mmol, 1.5 eq.) and benzyl chloroformate (39 μL, 0.26 mmol, 0.5 eq.)were added again. The mixture was stirred at r.t. for 18 hours. Thereaction was quenched with 1M aq. citric acid soln. (12 mL). The layerswere separated. The aq. phase was extracted with DCM (3×6 mL). The comb.org. phases were dried over MgSO₄ and concentrated in vacuo. To asolution of the crude ester in THF (2.3 mL), 1M aq. NaOH soln. (0.7 mL)was added. The solution was stirred at r.t. for 18 hours. The solutionwas diluted with water (2 mL), 1M aq. HCl soln. (0.7 mL), and DCM. Thelayers were separated and the aq. phase was extracted with DCM (2×). Thecomb. org. phases were concentrated in vacuo. The residue was dissolvedin DMF (1.2 mL), purified by prep. HPLC (column: Waters XBridge, 30×75mm, 10 um, UV/MS, acidic conditions), and concentrated in vacuo to givethe title compound as a pale yellow foam.

LC-MS 1FA: t_(R)=0.90 min; [M+H]⁺=443.2

Alkylation and Subsequent Saponification

(±)-4-(5-Chloro-2-hydroxy-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylicacid benzyl ester (40 mg, 0.1 mmol, 1 eq.) was dissolved in MeCN (0.4mL). (S)-2-(Toluene-4-sulfonyloxy)-propionic acid methyl ester (26 mg,0.1 mmol, 1 eq.) and potassium carbonate (28 mg, 0.2 mmol, 2 eq.) wereadded and the mixture was heated up to 65° C. and stirred at thattemperature for 18 hours. The mixture was allowed to cool down to r.t.and partitioned between water and DCM. The layers were separated overphase separators and the aq. phase was extracted with DCM (2×). Thecomb. org. layers were concentrated in vacuo. 2M aq. NaOH soln. (0.13mL) was added to a solution of the previous residue in MeCN (0.4 mL) andthe resulting mixture was stirred at r.t. for 1 hour 30. Formic acid(0.1 mL) was added and the mixture was purified by prep. HPLC (column:Waters XBridge, 30×75 mm, 10 um, UV/MS, acidic conditions) andevaporated to give the desired acid as a white solid.

Listed in Table 9 below are examples of compounds of Formula (I),prepared according to the above-mentioned method with the correspondingtosylate as starting material.

TABLE 9 t_(R) [min] MS-data Formula LC-MS m/z Example Compound ofFormula (I) MW Method [M + H]⁺ 119 (±)-4-[2-((R)-1-Carboxy-ethoxy)-5-C23H21N2O5ClS 1.01 473.2 chloro-phenyl]-6,7-dihydro-4H- 472.09 LC-MS 1FAthiazolo[5,4-c]pyridine-5- carboxylic acid benzyl ester 120(±)-4-[2-((S)-1-Carboxy-ethoxy)-5- C23H21N2O5ClS 1.01 473.2chloro-phenyl]-6,7-dihydro-4H- 472.09 LC-MS 1FAthiazolo[5,4-c]pyridine-5- carboxylic acid benzyl ester

Synthesis of Precursors and Intermediates Synthesis of2-(3-oxo-butyl)-isoindole-1,3-dione (C12H11NO3, MW=217.07)

To a well-stirred milky suspension of phthalimide (60.0 g, 408.0 mmol,1.00 eq.) and 3-buten-2-one (33.2 mL, 408.0 mmol, 1.00 eq.) in anhydrousethyl acetate (400 mL) under N₂, a freshly prepared yellow homogeneoussolution of sodium ethoxide (1.4 g, 20.4 mmol, 0.05 eq.) in anhydrousethanol (100 mL) was added dropwise (over 35 min.). After completion ofthe addition, the resulting slightly yellow heterogeneous mixture wasfurther stirred at r.t. for 2 hours. The beige heterogeneous mixture wasthen refluxed (oil bath temperature=90° C.) for 2 hours. The resultingorange homogeneous solution was then allowed to slowly cool down to r.t.The resulting heterogeneous mixture was concentrated to dryness in vacuoto afford a beige solid which was recrystallized from EtOH to afford thetitle compound as a beige solid.

LC-MS 3: t_(R)=0.67 min; [M+H]⁺=218.3

Synthesis of 2-(4-bromo-3-oxo-butyl)-isoindole-1,3-dione (C12H10NO3Br,MW=294.98)

To an ice-cooled and well-stirred suspension of2-(3-oxo-butyl)-isoindole-1,3-dione (30.0 g, 138 mmol, 1 eq.) in MeOH(180 mL), bromine (14.3 mL, 276 mmol, 2 eq.) was added in one portion.The resulting red heterogeneous mixture was stirred at 0° C. for 5 min.,and further at r.t. for 3.5 hours. The orange homogeneous reactionmixture was then treated with 10M aq. H₂SO₄ soln. (26.2 mL). Theresulting heterogeneous mixture was further stirred at r.t. for 2 hours.The resulting heterogeneous reaction mixture was filtered in order toisolate the target product as a white-off solid which was further driedunder high vacuum. The product was used without further purification.

LC-MS 3: t_(R)=0.76 min; [M+H]⁺=296.1

Synthesis of 2-[2-(2-Amino-thiazol-4-yl)-ethyl]-isoindole-1,3-dione(C13H11N3O2S, MW=273.06)

To a suspension of 2-(4-bromo-3-oxo-butyl)-isoindole-1,3-dione (29.93 g,74.2 mmol, 1 eq.) in acetone (450 mL) was added at r.t. (with rapidrate, use of a dropping-funnel) a suspension of thiourea (5.65 g, 74.2mmol, 1 eq.) in acetone (231 mL). The resulting suspension was furtherstirred at r.t. for 2 hours (heterogeneous mixture with a whiteprecipitate). The suspension was filtered and the isolated white solidwas washed with anhydrous acetone and then dried under hv to give theHBr salt of the title compound as a white solid. The product was usedwithout further purification.

LC-MS 3: t_(R)=0.52 min; [M+H]⁺=274.0

Synthesis of 4-(2-aminoethyl)thiazol-2-amine (C5H9N3S, MW=143.05)

A suspension of 2-[2-(2-amino-thiazol-4-yl)-ethyl]isoindole-1,3-dionehydrobromide (25.7 g, 72.6 mmol, 1 eq.) in water (125 mL) was treatedwith 62% hydrobromic acid in water (125 mL). The resulting suspensionwas then refluxed (oil bath temperature=120° C.), under N₂ for 18 hours.The resulting orange homogeneous reaction mixture was allowed to cooldown to r.t. (fast precipitation of a beige solid occurred). Theresulting suspension was filtered and the filter cake (phthalic acid)was washed with water. The obtained orange homogeneous filtrate was thenconcentrated in vacuo. The remaining water was finally removed byco-evaporation with toluene (repeated several times) and the obtainedresidue was further dried under hv to give the dihydrobromide salt ofthe title compound as an orange solid. The product was used withoutfurther purification.

LC-MS 3: t_(R)=0.13 min; [M+H]⁺=144.2

General Method for the Alkylation of a Phenol

Method A: To a mixture of 5-chlorosalicylaldehyde (25.0 g, 160 mmol, 1.0eq.) and potassium carbonate anhydrous (26.5 g, 192 mmol, 1.2 eq.) inDMF (100 mL), allyl bromide stabilized (15 mL, 176 mmol, 1.1 eq.) wasadded. The mixture was stirred at r.t. for 18 hours. The reactionmixture was poured in water (150 mL). The mixture was extracted withAcOEt (2×200 mL). The comb. org. phases were dried over MgSO₄ andconcentrated in vacuo to give the alkylated phenol as a yellow oil. Theproduct was used without further purification.

Listed in Table 10 below are derivatives 13b, prepared according to theabove-mentioned method, with corresponding phenol 14 as startingmaterial.

TABLE 10 t_(R) [min] Formula LC-MS MS-data m/z Derivatives 13b MW Method[M + H]⁺ 2-Allyloxy-5-chloro- C10H9O2Cl 0.88 No ionization benzaldehyde196.03 LC-MS 3 2-Allyloxy-5-fluoro- C10H9O2F 0.76 No ionizationbenzaldehyde 180.06 LC-MS 2

Method B: To a mixture of 5-chlorosalicylaldehyde (25.0 g, 160 mmol, 1.0eq.) and potassium carbonate anhydrous (33.1 g, 240 mmol, 1.5 eq.) inDMF (100 mL), ethyl bromoacetate (17.7 mL, 160 mmol, 1.0 eq.) was added.The mixture was stirred at r.t. for 5 hours. The reaction mixture waspoured in water (150 mL). The mixture was extracted with AcOEt (2×200mL). The comb. org. phases were dried over MgSO₄ and concentrated invacuo to give the desired ester as a yellow oil. The residue was usedwithout further purification.

Listed in Table 11 below are derivatives 13a, prepared according to theabove-mentioned method, with corresponding phenol 14 as startingmaterial.

TABLE 11 t_(R) [min] MS-data Formula LC-MS m/z Derivatives 13a MW Method[M + H]⁺ (4-Chloro-2-formyl-phenoxy)- C11H11O4Cl 0.84 No acetic acidethyl ester 242.04 LC-MS 3 ionization (4-Bromo-2-formyl-phenoxy)-C11H11O4Br 0.84 287.1 acetic acid ethyl ester 285.98 LC-MS 3

General Method for a Pictet Spengler Reaction

Method A: 2-Allyloxy-5-fluoro-benzaldehyde (320 mg, 1.78 mmol, 1.0 eq.)was added in one portion to a solution of4-(2-aminoethyl)thiazol-2-amine dihydrobromide (542 mg, 1.78 mmol, 1.0eq.) in 2M aq. NaOH (4 mL) and MeOH (11 mL). The resulting mixture washeated to 80° C. for 2 hours. The org. volatiles were removed in vacuoand the remaining aqueous phase was acidified with 2M aq. HCl soln. Themixture was washed with AcOEt (3×10 mL). The aq. layer was basified withaq. 25% NH₃ soln. and stirred with DCM (20 mL). The layers wereseparated and the aq. phase was extracted with DCM (3×20 mL). The comb.org. phases were dried over MgSO₄ and concentrated in vacuo to give thedesired amine as a yellow oil. The product was used without furtherpurification.

Listed in Table 12 below are derivatives 11b, prepared according to theabove-mentioned method, with corresponding benzaldehyde 13b as startingmaterial.

TABLE 12 t_(R) [min] MS-data Formula LC-MS m/z Derivatives 11b MW Method[M + H]⁺ (±)-4-(2-Allyloxy-5-fluoro-phenyl)- C15H16 0.38 305.94,5,6,7-tetrahydro-thiazolo[5,4- N3OFS LC-MS 2 c]pyridin-2-ylamine305.10 (±)-4-(2-Allyloxy-5-chloro-phenyl)- C15H16 0.53 321.94,5,6,7-tetrahydro-thiazolo[5,4- N3OClS LC-MS 3 c]pyridin-2-ylamine321.07

Method B: A mixture of 4-(2-aminoethyl)thiazol-2-amine dihydrobromide(3.75 g, 12.29 mmol, 1.0 eq.), (4-chloro-2-formyl-phenoxy)-acetic acidethyl ester (2.98 g, 12.29 mmol, 1.0 eq.) and NEt₃ (3.43 mL, 24.59 mmol,2.0 eq.) in ethanol (100 mL) was stirred at 80° C. for 18 hours. Theorg. volatiles were removed in vacuo and the residue was diluted withDCM (250 mL). The mixture was washed with sat. aq. NaHCO₃ soln. (1×100mL). The layers were separated. The aq. phase was extracted with DCM(2×50 mL). The comb. org. phases were dried over MgSO₄ and concentratedin vacuo to give the title compound as an yellow solid. The residue wasused without further purification.

Listed in Table 13 below are derivatives 11a, prepared according to theabove-mentioned method, with corresponding benzaldehyde 13a as startingmaterial.

TABLE 13 t_(R) [min] MS-data Formula LC-MS m/z Derivatives 11a MW Method[M + H]⁺ (±)-[2-(2-Amino-4,5,6,7-tetrahydro- C16H18 0.53 367.8thiazolo[5,4-c]pyridin-4-yl)-4-chloro- N3O3ClS LC-MS 3 phenoxy]-aceticacid ethyl ester 367.08 (±)-[2-(2-Amino-4,5,6,7-tetrahydro- C16H18 0.53412.0 thiazolo[5,4-c]pyridin-4-yl)-4-bromo- N3O3BrS LC-MS 3phenoxy]-acetic acid ethyl ester 411.03

General Method for the Boc-Protection of an Amine 11

To a solution under N₂ of(±)-4-(2-allyloxy-5-fluoro-phenyl)-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-ylamine(450 mg, 1.47 mmol, 1.00 eq.) and triethylamine (0.21 mL, 1.47 mmol,1.00 eq.) in DCM (5 mL), a solution of di-tert-butyl dicarbonate (328mg, 1.50 mmol, 1.02 eq.) in DCM (5 mL) was added dropwise. The mixturewas stirred at r.t. for 2.5 hours. The solvent was removed in vacuo andthe residue was partitioned between AcOEt and water. The layers wereseparated. The org. layer was washed once with water, dried over MgSO₄,and concentrated in vacuo to give the desired Boc-protected amine as ayellow solid. The product was used without further purification.

Listed in Table 14 below are Boc-protected amine 7, prepared accordingto the above-mentioned method, with corresponding amine 11 as startingmaterial.

TABLE 14 t_(R) [min] MS-data Formula LC-MS m/z Boc-protected amine 7 MWMethod [M + H]⁺ (±)-4-(2-Allyloxy-5-fluoro-phenyl)- C20H24 0.71 406.02-amino-6,7-dihydro-4H- N3O3FS LC-MS 2thiazolo[5,4-c]pyridine-5-carboxylic 405.15 acid tert-butyl ester(±)-4-(2-Allyloxy-5-chloro-phenyl)- C20H24 0.78 422.12-amino-6,7-dihydro-4H- N3O3ClS LC-MS 3thiazolo[5,4-c]pyridine-5-carboxylic 421.12 acid tert-butyl ester(±)-2-Amino-4-(5-chloro-2- C21H26 0.77 467.9ethoxycarbonylmethoxy-phenyl)- N3O5ClS LC-MS 36,7-dihydro-4H-thiazolo[5,4- 467.13 c]pyridine-5-carboxylic acid tert-butyl ester (±)-2-Amino-4-(5-bromo-2- C21H26 0.77 512.2ethoxycarbonylmethoxy-phenyl)- N3O5BrS LC-MS 36,7-dihydro-4H-thiazolo[5,4- 511.08 c]pyridine-5-carboxylic acid tert-butyl ester

General Method for a Cbz-Protection

To an ice-cooled solution of(±)-4-(2-allyloxy-5-chloro-phenyl)-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-ylamine(2.78 g, 4.6 mmol, 1.0 eq.) and triethylamine (1.91 mL, 13.7 mmol, 3.0eq.) in DCM (69 mL), benzyl chloroformate (0.76 mL, 5.0 mmol, 1.1 eq.)was added dropwise. Upon completion of the addition, the cooling bathwas removed and the suspension was stirred at r.t. for 18 hours. Thereaction was quenched with 1M aq. citric acid soln. (69 mL). The layerswere separated. The aq. phase was extracted with DCM (3×). The comb.org. phases were dried over MgSO₄, filtered, and concentrated in vacuo.The residue was purified by flashmaster (column: 340 g, flow: 90 mL/min,100 fractions of 45 mL, Heptane+AcOEt 50% to (AcOEt+NEt₃ 10%)100%) toyield the desired Cbz-protected compound as a brown solid.

Listed in Table 15 below are Cbz-protected amine, prepared according tothe above-mentioned method, with corresponding amine 11 or of Structure2 as starting material.

TABLE 15 t_(R) [min] MS-data Formula LC-MS m/z Cbz-protected amine 7 MWMethod [M + H]⁺ (±)-4-(2-Allyloxy-5-chloro- C23H22 0.79 456.2phenyl)-2-amino-6,7-dihydro-4H- N3O3ClS LC-MS 3thiazolo[5,4-c]pyridine-5-carboxylic 455.11 acid benzyl ester(±)-2-Amino-4-(5-chloro-2- C24H24 0.78 502.3ethoxycarbonylmethoxy-phenyl)-6,7- N3O5ClS LC-MS 3dihydro-4H-thiazolo[5,4-c]pyridine- 501.11 5-carboxylic acid benzylester (±)-4-(5-Chloro-2- C24H23 1.02 486.9ethoxycarbonylmethoxy-phenyl)-6,7- N2O5ClS LC-MS 3dihydro-4H-thiazolo[5,4-c]pyridine- 486.10 5-carboxylic acid benzylester

General Method for a Sandmeyer-Type Reaction

To a rapidly stirred solution of(±)-2-amino-4-(5-chloro-2-ethoxycarbonylmethoxy-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylicacid tert-butyl ester (5.05 g, 10.8 mmol, 1.00 eq.) in THF (50 mL)heated at 65° C., isoamyl nitrite (1.93 mL, 14.4 mmol, 1.33 eq.) wasadded dropwise under N₂. The resulting mixture was refluxed for 6 hours.The reaction mixture was allowed to cool to r.t. and concentrated invacuo. The residue was diluted with DCM (150 mL) and washed with water(2×125 mL). The org. layer was dried over MgSO₄ and concentrated invacuo. The residue was purified by flashmaster (column: 100 g, flow: 45mL/min, 40 fractions of 45 mL, Heptane+20% AcOEt to Heptane+75% AcOEt)to yield the desired thiazole derivative as a red oil.

Listed in Table 16 below are thiazole derivative 8 or of Structure 6-A,prepared according to the above-mentioned method, with correspondingaminothiazole 7 as starting material.

TABLE 16 t_(R) [min] MS-data Formula LC-MS m/z Intermediates 8 or ofStructure 6-A MW Method [M + H]⁺ (±)-4-(5-Chloro-2- C21H25 1.01 453.0ethoxycarbonylmethoxy-phenyl)-6,7- N2O5ClS LC-MS 3dihydro-4H-thiazolo[5,4- 452.12 c]pyridine-5-carboxylic acid tert- butylester (±)-4-(2-Allyloxy-5-chloro-phenyl)- C20H23 1.06 407.06,7-dihydro-4H-thiazolo[5,4- N2O3ClS LC-MS 3 c]pyridine-5-carboxylicacid tert- 406.11 butyl ester (±)-4-(2-Allyloxy-5-fluoro-phenyl)- C20H230.91 391.0 6,7-dihydro-4H-thiazolo[5,4- N2O3FS LC-MS 2c]pyridine-5-carboxylic acid tert- 390.14 butyl ester (±)-4-(5-Bromo-2-C21H25 1.02 496.9 ethoxycarbonylmethoxy-phenyl)-6,7- N2O5BrS LC-MS 3dihydro-4H-thiazolo[5,4- 496.07 c]pyridine-5-carboxylic acid tert- butylester (±)-4-(2-Allyloxy-5-chloro-phenyl)- C23H21 1.06 441.16,7-dihydro-4H-thiazolo[5,4- N2O3ClS LC-MS 3 c]pyridine-5-carboxylicacid 440.10 benzyl ester

General Method for a Sandmeyer Reaction

To a mixture of copper(II) bromide (7.24 g, 32.4 mmol, 1.5 eq.) andtert-butyl nitrite (4.28 mL, 32.4 mmol, 1.5 eq.) in MeCN (600 mL) underN₂ at r.t.,(±)-2-amino-4-(5-chloro-2-ethoxycarbonylmethoxy-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylicacid benzyl ester (10.85 g, 21.6 mmol, 1.0 eq.) was added portionwise. Aslow gas evolution started. After 20 min., the reaction mixture washeated to 55° C. (oil bath, preheated) for 15 min. to complete the gasevolution. The reaction mixture was allowed to cool down to r.t. andconcentrated in vacuo. The residue was purified by flashmaster (column:340 g, flow: 90 mL/min, 90 fractions of 45 mL, Heptane to Heptane+50%AcOEt) to yield the desired bromothiazole as a yellow oil.

Listed in Table 17 below are bromothiazole derivative 10, preparedaccording to the above-mentioned method, with correspondingaminothiazole 7a as starting material.

TABLE 17 t_(R) [min] MS-data Formula LC-MS m/z Bromothiazole derivatives10 MW Method [M + H]⁺ (±)-2-Bromo-4-(5-chloro-2- C24H22 1.04 565.1ethoxycarbonylmethoxy-phenyl)- N2O5BrClS LC-MS 36,7-dihydro-4H-thiazolo[5,4- 564.01 c]pyridine-5-carboxylic acid benzylester (±)-2-Bromo-4-(5-chloro-2- C21H24 1.05 530.7ethoxycarbonylmethoxy-phenyl)- N2O5BrClS LC-MS 36,7-dihydro-4H-thiazolo[5,4- 530.03 c]pyridine-5-carboxylic acidtert-butyl ester

Synthesis of(±)-4-(5-Cyano-2-ethoxycarbonylmethoxy-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylicacid tert-butyl ester (C22H25N3O5S, MW=443.15)

To a solution of(±)-4-(5-bromo-2-ethoxycarbonylmethoxy-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylicacid tert-butyl ester (375 mg, 0.75 mmol, 1.00 eq.) inN,N-dimethylacetamide (1.5 mL), zinc cyanide (44 mg, 0.37 mmol, 0.50eq.), tris(dibenzylideneacetone)dipalladium(O) (15 mg, 16 μmol, 0.02eq.), 1,1′-bis-(diphenylphosphino)-ferrocene (11 mg, 20 μmol, 0.03 eq.)and poly(methylhydrosiloxane) (15 μL) were added in sequence. Theresulting mixture was stirred at 150° C. under microwave irradiation for30 min. To the previous mixture, zinc cyanide (44 mg, 0.37 mmol, 0.50eq.), tris(dibenzylideneacetone)dipalladium(0) (15 mg, 16 μmol, 0.02eq.), 1,1′-bis-(diphenylphosphino)-ferrocene (11 mg, 20 μmol, 0.03 eq.)and poly(methylhydrosiloxane) (15 μL) were added. The resulting mixturewas stirred at 150° C. under microwave irradiation for 30 min. Thereaction mixture was diluted with AcOEt and water was added. The layerswere separated and the org. layer was dried over MgSO₄, filtered overcelite, and concentrated in vacuo. The residue, redissolved in DMF (4mL) and formic acid (0.2 mL), was purified by prep. HPLC (column: WatersXBridge, 30×75 mm, 10 um, UV/MS, acidic conditions) and evaporated togive the title compound as a brown oil.

LC-MS 3: t_(R)=0.95 min; [M+H]⁺=444.1

General Method for a Neghishi Cross-Coupling

Method A: To a solution under N₂ of(±)-2-bromo-4-(5-chloro-2-ethoxycarbonylmethoxy-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylicacid benzyl ester (100 mg, 0.18 mmol, 1.00 eq.) and 1.2M dimethylzinc intoluene (0.29 mL, 0.35 mmol, 2.00 eq.) in THF (10 mL),tetrakis(triphenylphosphine) palladium (0) (10.2 mg, 9 μmol, 0.05 eq.)was added. The mixture was stirred at 50° C. for 18 hours. The mixturewas allowed to cool to r.t. and concentrated in vacuo. The residue wasdiluted with DCM (50 mL) and washed with water (2×25 mL). The org. layerwas dried over MgSO₄ and concentrated in vacuo. The residue was taken upin DMF, filtered, and then purified by prep. HPLC (column: Atlantis,30×75 mm, 10 um, UV/MS, acidic conditions) and concentrated in vacuo togive the desired compound as a brown oil.

Listed in Table 18 below are derivatives of Structure 6-B, preparedaccording to the above-mentioned method, with corresponding dialkylzincreagent as starting material.

TABLE 18 t_(R) [mm] MS-data Formula LC-MS m/z Intermediates of Structure6-B MW Method [M + H]⁺ (±)-4-(5-Chloro-2- C25H25 1.02 501.1ethoxycarbonylmethoxy-phenyl)-2- N2O5ClS LC-MS 3methyl-6,7-dihydro-4H-thiazolo[5,4- 500.12 c]pyridine-5-carboxylic acidbenzyl ester (±)-4-(5-Chloro-2- C26H27 1.02 515.1ethoxycarbonylmethoxy-phenyl)-2- N2O5ClS LC-MS 3ethyl-6,7-dihydro-4H-thiazolo[5,4- 514.13 c]pyridine-5-carboxylic acidbenzyl ester

Method B: Synthesis of(±)-4-(5-Chloro-2-ethoxycarbonylmethoxy-phenyl)-2-cyclopropyl-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylicacid benzyl ester (C27H27N2O5ClS, MW=526.13): To a solution under N₂ of(±)-2-bromo-4-(5-chloro-2-ethoxycarbonylmethoxy-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylicacid benzyl ester (100 mg, 0.18 mmol, 1.00 eq.) and 0.5M cyclopropylzincbromide in THF (0.7 mL, 0.35 mmol, 2.00 eq.) in THF (10 mL),tetrakis(triphenylphosphine) palladium (0) (10.2 mg, 9 μmol was added.The mixture was stirred at 50° C. for 18 hours. The mixture was allowedto cool to r.t. and concentrated in vacuo. The residue was diluted withDCM (50 mL) and washed with water (2×25 mL). The org. layer was driedover MgSO₄ and concentrated in vacuo. The residue was taken up in DMF,filtered, and then purified by prep. HPLC (column: Atlantis, 30×75 mm,10 um, UV/MS, acidic conditions) and concentrated in vacuo to give thetitle compound.

LC-MS 3: t_(R)=1.02 min; [M+H]⁺=527.1

Synthesis of(±)-4-(5-Chloro-2-ethoxycarbonylmethoxy-phenyl)-2-trifluoromethyl-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylicacid benzyl ester (C25H22N2O5ClF3S, MW=554.09

To a solution of(±)-2-bromo-4-(5-chloro-2-ethoxycarbonylmethoxy-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylicacid benzyl ester (50 mg, 0.09 mmol, 1.00 eq.) in DMF (1 mL), copper(I)iodide (68 mg, 0.35 mmol, 5.00 eq.), triphenylarsine (8.7 mg, 0.02 mmol,0.40 eq.), tris(dibenzylidenaceton)di-palladium-(0)-chloroform adduct(3.7 mg, 3.5 μmol, 0.05 eq.) and methyl2,2-difluoro-2-(fluorosulfonyl)acetate (46 μL, 0.35 mmol, 5.00 eq.) wereadded in sequence. The resulting suspension was heated at 100° C. for 18hours. The mixture was allowed to cool to r.t. and concentrated invacuo. The residue was taken up in DMF, filtered, and then purified byprep. HPLC (column: Atlantis, 30×75 mm, 10 um, UV/MS, acidic conditions)and concentrated in vacuo to afford the title compound as an yellow oil.

LC-MS 3: t_(R)=1.05 min; [M+H]⁺=555.1

Synthesis of5-Chloro-2-hydroxy-N-[2-(2-isopropyl-thiazol-4-yl)-ethyl]-benzamide(C15H17N2O2ClS, MW=324.07)

To a solution of 5-chlorosalicylic acid (863 mg, 5.0 mmol, 1.0 eq.) inTHF (3 mL) and water (4 mL), 1-hydroxybenzotriazole hydrate (1.01 g, 7.5mmol, 1.5 eq.) was added. The resulting solution was stirred at r.t. for30 minutes. Then 2-(2-isopropyl-1,3-thiazol-4-yl)ethanaminehydrochloride (1.03 g, 5.0 mmol, 1.0 eq.) in THF (3 mL) and NEt₃ (1.39mL, 10.0 mmol, 2.0 eq) andN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.44 g,7.5 mmol, 1.5 eq) in water (4 mL) were added in sequence. The resultingmixture was stirred at r.t. for 18 hours. The reaction mixture waspoured in sat. aq. NaHCO₃ (75 mL). The mixture was extracted with AcOEt(2×50 mL). The comb. org. phases were washed with 1M aq. HCl soln. (50mL) and sat. aq. NaCl soln. (1×20 mL), dried over MgSO₄, andconcentrated in vacuo to give the desired amide as a brown oil. Theproduct was used without further purification.

LC-MS 3: t_(R)=0.86 min; [M+H]⁺=325.0

Synthesis of{4-Chloro-2-[2-(2-isopropyl-thiazol-4-yl)-ethylcarbamoyl]-phenoxy}-aceticacid ethyl ester (C19H23N2O4ClS, MW=410.11)

To a mixture of5-chloro-2-hydroxy-N-[2-(2-isopropyl-thiazol-4-yl)-ethyl]-benzamide (400mg, 1.23 mmol, 1.00 eq.) and potassium carbonate anhydrous (340 mg, 2.46mmol, 2.00 eq.) in acetone (20 mL), ethyl bromoacetate (0.14 mL, 1.29mmol, 1.05 eq.) was added. The mixture was stirred at r.t. for 5 hours.The reaction mixture was poured in water (50 mL). The mixture wasextracted with AcOEt (2×20 mL). The comb. org. phases were dried overMgSO₄ and concentrated in vacuo. The residue was purified by flashmaster(column: 25 g, flow: 30 mL/min, 45 fractions of 15 mL, Heptane+20% AcOEtto Heptane+80% AcOEt) to yield the ester as a white solid.

LC-MS 3: t_(R)=0.87 min; [M+H]⁺=411.1

Synthesis of(±)-4-(5-Chloro-2-ethoxycarbonylmethoxy-phenyl)-2-isopropyl-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylicacid benzyl ester (C27H29N2O5ClS, MW=528.15)

Step 1: A mixture of{4-chloro-2-[2-(2-isopropyl-thiazol-4-yl)-ethylcarbamoyl]-phenoxy}-aceticacid ethyl ester (100 mg, 0.24 mmol, 1 eq.) and POCl₃ (0.34 mL, 3.65mmol, 15 eq.) in MeCN (2 mL) was stirred at 80° C. for 18 hours. Themixture was allowed to cool down to r.t. and concentrated in vacuo. Theresidue was purified by prep. HPLC (column: Atlantis, 30×75 mm, 10 um,UV/MS, acidic conditions) and concentrated in vacuo to give ethyl2-(4-chloro-2-(2-isopropyl-6,7-dihydrothiazolo[5,4-c]pyridin-4-yl)phenoxy)acetateas a yellow oil.

LC-MS 3: t_(R)=0.72 min; [M+H]⁺=393.2

Step 2: To an ice-cooled solution of ethyl2-(4-chloro-2-(2-isopropyl-6,7-dihydrothiazolo[5,4-c]pyridin-4-yl)phenoxy)acetate(33 mg, 84 μmol, 1.0 eq.) in EtOH (5 mL), NaBH₄ (3.5 mg, 92 μmol, 1.1eq.) was added. The cooling bath was removed and the yellow solution wasstirred at r.t. for 2 hours. The reaction mixture was poured in water(15 mL). The mixture was extracted with DCM (2×20 mL). The comb. org.phases were dried over MgSO₄ and concentrated in vacuo. To an-ice cooledsolution of the residue and DIPEA (43 μL, 252 μmol, 3.0 eq.) in DCM (5mL), benzyl chloroformate (14 μL, 92 μmol, 1.1 eq.) was added dropwise.Upon completion of the addition, the cooling bath was removed and thesolution was stirred at r.t. for 1 hour. The reaction was quenched with1M aq. citric acid soln. (5 mL). The layers were separated. The aq.phase was extracted with DCM (3×5 mL). The comb. org. phases were driedover MgSO₄ and concentrated in vacuo. The residue was purified by prep.HPLC (column: Atlantis, 30×75 mm, 10 um, UV/MS, acidic conditions) andconcentrated in vacuo to afford the title compound as a yellow oil.

LC-MS 3: t_(R)=1.02 min; [M+H]⁺=528.9

General Method for a Boc-Deprotection

To an ice-cooled solution of(R)-4-(5-chloro-2-ethoxycarbonylmethoxy-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylicacid tert-butyl ester in EtOH (75 mL), 4M HCl in dioxane (25 mL) wasadded. The resulting solution was stirred at r.t. for 18 hours. Thereaction mixture was concentrated in vacuo to give the hydrochloridesalt of the deprotected amine. The product was used without furtherpurification.

Listed in Table 19 below are amines of Structure 2 (or the correspondingsalt), prepared according to the above-mentioned method, with thecorresponding Boc-protected amine as starting material.

TABLE 19 t_(R) [min] MS-data Formula LC-MS m/z Amines of Structure 2 MWMethod [M + H]⁺ ((R)-4-Chloro-2-4,5,6,7-tetrahydro- C16H17 0.61 353.0thiazolo[5,4-c]pyridin-4-yl- N2O3ClS LC-MS 3 phenoxy)-acetic acid ethylester 352.07 hydrochloride ((S)-4-Chloro-2-4,5,6,7-tetrahydro- C16H170.61 353.0 thiazolo[5,4-c]pyridin-4-yl- N2O3ClS LC-MS 3 phenoxy)-aceticacid ethyl ester 352.07 hydrochloride(±)-[4-Chloro-2-(4,5,6,7-tetrahydro- C16H17 0.60 353.0thiazolo[5,4-c]pyridin-4-yl)- N2O3ClS LC-MS 3 phenoxy]-acetic acid ethylester 352.07 hydrochloride

Synthesis of(±)-[4-Chloro-2-(4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4-yl)-phenoxyl]-aceticacid isopropyl ester (C17H19N2O3ClS, MW=366.08)

To a solution of(±)-[4-chloro-2-(4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4-yl)-phenoxy]-aceticacid ethyl ester hydrochloride (1.70 g, 4.37 mmol, 1 eq.) in THF (50 mL)and EtOH (25 mL), 1M aq. NaOH (50 mL) was added. The pale yellowsolution was stirred at r.t. for 18 hours, then concentrated in vacuo.The resulting aq. layer was carefully acidified with 2N aq. HCl. Themixture was extracted with DCM (3×100 mL). The comb. org. phases weredried over MgSO₄ and concentrated in vacuo. The residue was dissolved in5-6N HCl in 2-propanol (150 mL). The reaction mixture was stirred atr.t. for 18 hours. The mixture was concentrated in vacuo. The reactionwas diluted with sat. aq. NaHCO₃ (250 mL). The mixture was extractedwith DCM (3×200 mL). The comb. org. phases were dried over MgSO₄ andconcentrated in vacuo to give the title compound as a yellow solid. Theproduct was used without further purification.

LC-MS 3: t_(R)=0.65 min; [M+H]⁺=367.1

General Method for the Synthesis of a 4-Nitrophenol Carbamate

To a solution of(±)-[4-chloro-2-(4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4-yl)-phenoxy]-aceticacid isopropyl ester (1.40 g, 3.82 mmol, 1.0 eq.) andN-ethyldiisopropylamine (1.63 mL, 9.54 mmol, 2.5 eq.) in DCM (50 mL),4-nitrophenyl chloroformate (846 mg, 4.2 mmol, 1.1 eq.) was added. Themixture was stirred at r.t. for 1 hour. The reaction was quenched with1M aq. citric acid soln. (50 mL). The layers were separated. The aq.phase was extracted with DCM (3×100 mL). The comb. org. phases weredried over MgSO₄, filtered, and concentrated in vacuo. The residue waspurified by flashmaster (column: 100 g, flow: 45 mL/min, 30 fractions of45 mL, Heptane+20% AcOEt to Heptane+80% AcOEt) to yield the desiredcarbamate as a white solid.

Listed in Table 20 below are 4-nitrophenol carbamate 5, preparedaccording to the above-mentioned method, with the corresponding amine ofStructure 2 (or the corresponding salt) as starting material.

TABLE 20 t_(R) [min] MS-data Formula LC-MS m/z 4-Nitrophenol carbamate 5MW Method [M + H]⁺ (±)-4-(5-Chloro-2- C24H22 1.03 532.1isopropoxycarbonylmethoxy-phenyl)- N3O7ClS LC-MS 36,7-dihydro-4H-thiazolo[5,4- 531.09 c]pyridine-5-carboxylic acid 4-nitro-phenyl ester (R)-4-(5-Chloro-2- C23H20 1.00 518.1ethoxycarbonylmethoxy-phenyl)- N3O7ClS LC-MS 36,7-dihydro-4H-thiazolo[5,4- 517.07 c]pyridine-5-carboxylic acid 4-nitro-phenyl ester

General Method for the Cleavage of an Allyl Protecting Group

A mixture under N₂ of(±)-4-(2-allyloxy-5-chloro-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylicacid benzyl ester (530 mg, 1.2 mmol, 1.00 eq.), 1,3-dimethylbarbituricacid (379 mg, 2.4 mmol, 2.00 eq.) and tetrakis(triphenylphosphine)palladium (0) (69 mg, 60 μmol, 0.05 eq.) in MeOH (24 mL) was stirred atr.t. for 3 hours. The mixture was partitioned between AcOEt (150 mL) andwater (150 mL). The layers were separated and the aq. phase wasextracted with AcOEt (2×150 mL). The comb. org. phases were washed withsat. aq. NaCl soln. (1×150 mL), dried over MgSO₄, filtered over celite,and concentrated in vacuo. The residue was purified by flashmaster(column: 100 g, flow: 45 mL/min, 45 fractions of 45 mL, Heptane+5% AcOEtto Heptane+50% AcOEt) to yield the desired phenol as a yellow oil.

Listed in Table 21 below are phenols 9, prepared according to theabove-mentioned method, with the corresponding allyl protected phenol 8as starting material.

TABLE 21 t_(R) [min] MS-data Formula LC-MS m/z Phenols 9 MW Method [M +H]⁺ (±)-4-(5-Chloro-2-hydroxy-phenyl)- C20H17 0.94 401.06,7-dihydro-4H-thiazolo[5,4- N2O3ClS LC-MS 3 c]pyridine-5-carboxylicacid benzyl 400.07 ester (±)-4-(5-Chloro-2-hydroxy-phenyl)- C17H19 0.95367.0 6,7-dihydro-4H-thiazolo[5,4- N2O3ClS LC-MS 3c]pyridine-5-carboxylic acid tert- 366.08 butyl ester

Synthesis of(±)-4-(2-Ethoxycarbonylmethoxy-5-fluoro-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylicacid tert-butyl ester (C21H25N205FS, MW=436.15)

A mixture under N₂ of(±)-4-(2-allyloxy-5-fluoro-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylicacid tert-butyl ester (261 mg, 0.61 mmol, 1.00 eq.),1,3-dimethylbarbituric acid (191 mg, 1.21 mmol, 2.00 eq.) andtetrakis(triphenylphosphine) palladium (0) (35 mg, 30 μmol, 0.05 eq.) inMeOH (12 mL) was stirred at r.t. for 18 hours. The mixture waspartitioned between AcOEt (55 mL) and water (55 mL). The layers wereseparated and the aq. phase was extracted with AcOEt (2×55 mL). Thecomb. org. phases were washed with sat. aq. NaCl soln. (1×55 mL), driedover MgSO₄, and concentrated in vacuo. To a solution of the resultingcrude phenol and potassium carbonate (252 mg, 1.82 mmol, 3.00 eq.) inDMF (2.1 mL), ethyl bromoacetate (0.1 mL, 0.91 mmol, 1.50 eq.) wasadded. The mixture was stirred at r.t. for 18 hours. Ethyl bromoacetate(50 μL, 0.46 mmol, 1.33 eq.) was added again and the mixture was stirredat r.t. for 7 hours. LC/MS still showed starting material. Ethylbromoacetate (67 μL, 0.61 mmol, 1.00 eq.) and potassium carbonate (126mg, 0.91 mmol, 1.50 eq.) were added again and the mixture was stirred atr.t. for 18 hours. The reaction mixture was diluted with AcOEt andwater. The layers were separated and the aq. phase was extracted withAcOEt (2×). The comb. org. extracts were washed with water and sat. aq.NaCl soln., dried over MgSO₄, filtered, and concentrated in vacuo. Theresidue was purified by flashmaster (column: 50 g, flow: 30 mL/min, 50fractions of 30 mL, Heptane to Heptane+40% AcOEt) to yield the titlecompound as an orange oil.

LC-MS 3: t_(R)=0.98 min; [M+H]⁺=437.1

Synthesis of(±)-4-(5-Chloro-2-ethoxycarbonylmethoxy-phenyl)-2-(cyclopropanecarbonyl-amino)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylicacid benzyl ester

(C28H28N3O6ClS, MW=569.14)

To a solution of cyclopropanecarboxylic acid (5 μL, 60 μmol, 1 eq.) inDMF (5 mL), DIPEA (51 μL, 300 μmol, 5 eq.) and TBTU (19 mg, 60 μmol, 1eq.) were added in sequence. The resulting solution was stirred at r.t.for 30 minutes. Then(±)-2-amino-4-(5-chloro-2-ethoxycarbonylmethoxy-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylicacid benzyl ester (30 mg, 60 μmol, 1 eq.) was added and the resultingmixture was stirred at r.t. for 18 hours. The reaction mixture wasconcentrated in vacuo. The residue was purified by prep. HPLC (column:Atlantis, 30×75 mm, 10 um, UV/MS, acidic conditions) and concentrated invacuo to give the title compound as a colorless oil.

LC-MS 3: t_(R)=0.98 min; [M+H]⁺=570.3

Synthesis of(±)-2-Acetylamino-4-(5-chloro-2-ethoxycarbonylmethoxy-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylicacid benzyl ester (C26H26N3O6ClS, MW=543.12)

To an-ice cooled solution of(±)-2-amino-4-(5-chloro-2-ethoxycarbonylmethoxy-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylicacid benzyl ester (50 mg, 100 μmol, 1 eq.) and NEt₃ (69 μL, 500 μmol, 5eq.) in DCM (1 mL), acetyl chloride (14 μL, 200 μmol, 2 eq.)

was added dropwise. Upon completion of the addition, the cooling bathwas removed and the solution was stirred at r.t. for 3 hours. Thesolvent was removed in vacuo. The residue was purified by prep. HPLC(column: Atlantis, 30×75 mm, 10 um, UV/MS, acidic conditions) andconcentrated in vacuo to give the title compound as a colorless oil.

LC-MS 3: t_(R)=0.94 min; [M+H]⁺=544.4

General Method for an Amide Coupling

Method A: To a solution of trans-2-phenylcyclopropane-1-carboxylic acid(81 mg, 0.5 mmol, 1 eq.) in DMF (4 mL), DIPEA (0.43 mL, 2.5 mmol, 5 eq.)and TBTU (161 mg, 0.5 mmol, 1 eq.) were added in sequence. The resultingsolution was stirred at r.t. for 30 min. Then((R)-4-chloro-2-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4-yl-phenoxy)-aceticacid ethyl ester dihydrobromide (257 mg, 0.5 mmol, 1 eq.) was added andthe resulting mixture was stirred at r.t. for 18 hours. The mixture wasconcentrated in vacuo. The residue was purified by prep. HPLC (column:Atlantis, 30×75 mm, 10 um, UV/MS, acidic conditions) and concentrated invacuo to give the desired amide as a yellow oil.

Listed in Table 22 below are compounds of Structure 1, preparedaccording to the above-mentioned method, with corresponding compound ofStructure 2 (or the corresponding salt) and the corresponding carboxylicacid as starting materials.

TABLE 22 t_(R) [min] MS-data Formula LC-MS m/z Compounds of Structure 1MW Method [M + H]⁺ {4-Chloro-2-[(R)-5-(trans-2- C26H25 1.02 497.0phenyl-cyclopropanecarbonyl)- N2O4ClS LC-MS 34,5,6,7-tetrahydro-thiazolo[5,4- 496.12 c]pyridin-4-yl]-phenoxy}-aceticacid ethyl ester (4-Chloro-2-{(R)-5-[trans-2- C26H24 1.03 515.1(3-fluoro-phenyl)- N2O4ClFS LC-MS 3 cyclopropanecarbonyl]-4,5,6,7-514.11 tetrahydro-thiazolo[5,4- c]pyridin-4-yl}-phenoxy)-acetic acidethyl ester (4-Chloro-2-{(R)-5-[trans-2- C26H24 1.02 515.1(4-fluoro-phenyl)- N2O4ClFS LC-MS 3 cyclopropanecarbonyl]-4,5,6,7-514.11 tetrahydro-thiazolo[5,4- c]pyridin-4-yl}-phenoxy)-acetic acidethyl ester {4-Chloro-2-[(±)-2-methyl-5- C27H27 1.03 511.3((1R,2R)-2-phenyl- N2O4ClS LC-MS 3 cyclopropanecarbonyl)-4,5,6,7- 510.14tetrahydro-thiazolo[5,4- c]pyridin-4-yl]-phenoxy}-acetic acid ethylester

General Method for an Urea Synthesis

To a solution of(±)-[4-chloro-2-(4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4-yl)-phenoxy]-aceticacid ethyl ester hydrochloride (50 mg, 0.13 mmol, 1.00 eq.) and NEt₃ (54μL, 0.39 mmol, 3.00 eq.) in MeCN (1 mL), 2-fluorobenzyl isocyanate (20mg, 0.14 mmol, 1.05 eq.) in MeCN (1 mL) was added. The mixture wasstirred at r.t. for 18 hours. The solution was neutralized with formicacid and purified by prep. HPLC (column: Atlantis, 30×75 mm, 10 um,UV/MS, acidic conditions) and concentrated in vacuo to give the desiredurea as an yellow oil.

Listed in Table 23 below are compounds of Structure 1, preparedaccording to the above-mentioned method, with corresponding compound ofStructure 2 (or the corresponding salt) and the corresponding isocyanateas starting materials.

TABLE 23 t_(R) [min] MS-data Formula LC-MS m/z Intermediates ofStructure 1 MW Method [M + H]⁺ (±)-{4-Chloro-2-[5-(2-fluoro- C24H23 0.98504.3 benzylcarbamoyl)-4,5,6,7- N3O4ClFS LC-MS 3tetrahydro-thiazolo[5,4-c]pyridin- 503.11 4-yl]-phenoxy}-acetic acidethyl ester (±)-{4-Chloro-2-[5-(3-fluoro- C24H23 0.98 504.3benzylcarbamoyl)-4,5,6,7- N3O4ClFS LC-MS 3tetrahydro-thiazolo[5,4-c]pyridin- 503.11 4-yl]-phenoxy}-acetic acidethyl ester (±)-{4-Chloro-2-[5-(4-fluoro- C24H23 0.98 504.3benzylcarbamoyl)-4,5,6,7- N3O4ClFS LC-MS 3tetrahydro-thiazolo[5,4-c]pyridin- 503.11 4-yl]-phenoxy}-acetic acidethyl ester (±)-[2-(5-Benzylcarbamoyl- C24H24 0.97 486.34,5,6,7-tetrahydro-thiazolo[5,4- N3O4ClS LC-MS 3c]pyridin-4-yl)-4-chloro-phenoxy]- 485.12 acetic acid ethyl ester

Chiral Separation

Listed in table 24 are enantiomers or diastereoisomers which wereseparated by prep. HPLC over a chiral stationary phase. Conditions forthe separation are:

Method CS1: Column (R,R) Whelk-01 (21×250 mm, 5 μm), eluent A 50%Heptane and eluent B 50% EtOH, flow 16 mL/min.

Method CS2: Column Daicel ChiralPak IA (30×250 mm, 5 μm), eluent A 90%MeCN and eluent B 10% EtOH (with 0.1% DEA), flow 34 mL/min.

Method CS3: Column (R,R) Whelk-01 (21×250 mm, 5 μm), eluent A 10%Heptane and eluent B 90% EtOH, flow 16 mL/min.

Method CS4: Column Daicel ChiralPak IC (20×250 mm, 5 μm), eluent A 70%Heptane and eluent B 30% EtOH, flow 16 mL/min.

TABLE 24 Formula t_(R) [min] MW LC-MS Method Optically pure HPLC MS-datam/z Mixture intermediates Method [M + H]⁺ {4-Chloro-2-[(R)-5-(trans-2-{4-Chloro-2-[(R)-5-((1R,2R)- C26H25 1.02 phenyl- 2-phenyl- N2O4ClS LC-MS3 cyclopropanecarbonyl)- cyclopropanecarbonyl)- 496.12 497.04,5,6,7-tetrahydro- 4,5,6,7-tetrahydro- CS1thiazolo[5,4-c]pyridin-4-yl]- thiazolo[5,4-c]pyridin-4-yl]-phenoxy}-acetic acid ethyl phenoxy}-acetic acid ethyl ester ester{4-Chloro-2-[(R)-5-(trans-2- {4-Chloro-2-[(R)-5-((1S,2S)- C26H25 1.02phenyl- 2-phenyl- N2O4ClS LC-MS 3 cyclopropanecarbonyl)-cyclopropanecarbonyl)- 496.12 497.0 4,5,6,7-tetrahydro-4,5,6,7-tetrahydro- CS1 thiazolo[5,4-c]pyridin-4-yl]-thiazolo[5,4-c]pyridin-4-yl]- phenoxy}-acetic acid ethyl phenoxy}-aceticacid ethyl ester ester (4-Chloro-2-{(R)-5-[trans-2-(4-Chloro-2-{(R)-5-[(1R,2R)- C26H24 1.03 (3-fluoro-phenyl)-2-(3-fluoro-phenyl)- N2O4ClFS LC-MS 3 cyclopropanecarbonyl]-cyclopropanecarbonyl]- 514.11 515.1 4,5,6,7-tetrahydro-4,5,6,7-tetrahydro- CS1 thiazolo[5,4-c]pyridin-4-yl}-thiazolo[5,4-c]pyridin-4-yl}- phenoxy)-acetic acid ethyl phenoxy)-aceticacid ethyl ester ester (4-Chloro-2-{(R)-5-[trans-2-(4-Chloro-2-{(R)-5-[(1S,2S)- C26H24 1.03 (3-fluoro-phenyl)-2-(3-fluoro-phenyl)- N2O4ClFS LC-MS 3 cyclopropanecarbonyl]-cyclopropanecarbonyl]- 514.11 515.1 4,5,6,7-tetrahydro-4,5,6,7-tetrahydro- CS1 thiazolo[5,4-c]pyridin-4-yl}-thiazolo[5,4-c]pyridin-4-yl}- phenoxy)-acetic acid ethyl phenoxy)-aceticacid ethyl ester ester (4-Chloro-2-{(R)-5-[trans-2-(4-Chloro-2-{(R)-5-[(1R,2R)- C26H24 1.02 (4-fluoro-phenyl)-2-(4-fluoro-phenyl)- N2O4ClFS LC-MS 3 cyclopropanecarbonyl]-cyclopropanecarbonyl]- 514.11 515.1 4,5,6,7-tetrahydro-4,5,6,7-tetrahydro- CS1 thiazolo[5,4-c]pyridin-4-yl}-thiazolo[5,4-c]pyridin-4-yl}- phenoxy)-acetic acid ethyl phenoxy)-aceticacid ethyl ester ester (4-Chloro-2-{(R)-5-[trans-2-(4-Chloro-2-{(R)-5-[(1S,2S)- C26H24 1.02 (4-fluoro-phenyl)-2-(4-fluoro-phenyl)- N2O4ClFS LC-MS 3 cyclopropanecarbonyl]-cyclopropanecarbonyl]- 514.11 515.1 4,5,6,7-tetrahydro-4,5,6,7-tetrahydro- CS1 thiazolo[5,4-c]pyridin-4-yl}-thiazolo[5,4-c]pyridin-4-yl}- phenoxy)-acetic acid ethyl phenoxy)-aceticacid ethyl ester ester (±)-4-(5-Chloro-2- (R)-4-(5-Chloro-2- C24H23 1.03ethoxycarbonylmethoxy- ethoxycarbonylmethoxy- N2O5ClS LC-MS 3phenyl)-6,7-dihydro-4H- phenyl)-6,7-dihydro-4H- 486.10 486.9thiazolo[5,4-c]pyridine-5- thiazolo[5,4-c]pyridine-5- CS2 carboxylicacid benzyl ester carboxylic acid benzyl ester (±)-4-(5-Chloro-2-(S)-4-(5-Chloro-2- C24H23 1.03 ethoxycarbonylmethoxy-ethoxycarbonylmethoxy- N2O5ClS LC-MS 3 phenyl)-6,7-dihydro-4H-phenyl)-6,7-dihydro-4H- 486.10 486.9 thiazolo[5,4-c]pyridine-5-thiazolo[5,4-c]pyridine-5- CS2 carboxylic acid benzyl ester carboxylicacid benzyl ester {4-Chloro-2-[(±)-2-methyl-5-{4-Chloro-2-[(R)-2-methyl-5- C27H27 1.03 ((1R,2R)-2-phenyl-((1R,2R)-2-phenyl- N2O4ClS LC-MS 3 cyclopropanecarbonyl)-cyclopropanecarbonyl)- 510.14 511.3 4,5,6,7-tetrahydro-4,5,6,7-tetrahydro- CS3 thiazolo[5,4-c]pyridin-4-yl]-thiazolo[5,4-c]pyridin-4-yl]- phenoxy}-acetic acid ethyl phenoxy}-aceticacid ethyl ester ester {4-Chloro-2-[(±)-2-methyl-5-{4-Chloro-2-[(S)-2-methyl-5- C27H27 1.03 ((1R,2R)-2-phenyl-((1R,2R)-2-phenyl- N2O4ClS LC-MS 3 cyclopropanecarbonyl)-cyclopropanecarbonyl)- 510.14 511.3 4,5,6,7-tetrahydro-4,5,6,7-tetrahydro- CS3 thiazolo[5,4-c]pyridin-4-yl]-thiazolo[5,4-c]pyridin-4-yl]- phenoxy}-acetic acid ethyl phenoxy}-aceticacid ethyl ester ester (±)-4-(5-Chloro-2- (R)-4-(5-Chloro-2- C21H25 1.01ethoxycarbonylmethoxy- ethoxycarbonylmethoxy- N2O5ClS LC-MS 3phenyl)-6,7-dihydro-4H- phenyl)-6,7-dihydro-4H- 452.12 453.0thiazolo[5,4-c]pyridine-5- thiazolo[5,4-c]pyridine-5- CS4 carboxylicacid tert-butyl carboxylic acid tert-butyl ester ester(±)-4-(5-Chloro-2- (S)-4-(5-Chloro-2- C21H25 1.01 ethoxycarbonylmethoxy-ethoxycarbonylmethoxy- N2O5ClS LC-MS 3 phenyl)-6,7-dihydro-4H-phenyl)-6,7-dihydro-4H- 452.12 453.0 thiazolo[5,4-c]pyridine-5-thiazolo[5,4-c]pyridine-5- CS4 carboxylic acid tert-butyl carboxylicacid tert-butyl ester ester

Biological Assays:

Preparation of hCRTH2 Receptor Membranes and Radioligand DisplacementAssay:

First, recombinant HEK293-hCRTH₂ cells were detached from culture platesinto 5 ml buffer A/plate (Buffer A: 5 mM Tris, 1 mM MgCl₂-6H₂O pH=7.4)using a rubber policeman. Cells were then transferred intocentrifugation tubes and centrifuged for 5 min at 400 g. The cell pelletwas resuspended in the same buffer and tubes were frozen at −80° C.Cells were thawed and membrane fragments were generated byhomogenization using a polytron homogenizer (30 seconds). The membranefragments were then centrifuged at 3000 g for 20 minutes and resuspendedin buffer C (Buffer C: 75 mM Tris, 25 mM MgCl₂, 250 mM Saccharose pH7.4). Aliquots of membrane fragments were stored at −20° C.

Binding assay was performed in a final assay volume of 250 μl. First, 25μl of test compound, previously diluted in Binding-Buffer(Binding-Buffer: 50 mM Tris-Base, 100 mM NaCl, 1 mM EDTA, 0.1% BSA(protease free), 0.01% NaN₃, 10 mM MnCl₂, pH 7.0) was placed into eachwell. After addition of 75 μl Binding-Buffer, 50 μl of the radioligand³H-PGD₂ (at 2.5 nM (220.000 dpm/well) from ANAWA ART0662) was added toeach well. Binding assay was started by addition of 100 μl CRTH₂membrane fragments, reaching a final concentration of 20 μg/well. Fornon-specific binding, PGD₂ was added to the reaction mixture to 10 mMfinal concentration. This assay mix was incubated for 90 minutes at roomtemperature and then filtered through a GF/C filter 96-well plate whichwas pre-soaked for 3 hours in 0.5% polyethyleneimine (PEI). Thefilter-wells were washed three times with ice cold Binding-Buffer. Then,40 μl of Microscint-40 (Packard) was added to each well and the retainedradioactivity quantified in a Topcount (Packard).

Antagonistic activities of exemplified compounds are displayed in thefollowing Table:

IC₅₀ Example Name [nM] 1(±)-{4-Chloro-2-[5-(2-fluoro-benzylcarbamoyl)-4,5,6,7-tetrahydro- 9.4thiazolo[5,4-c]pyridin-4-yl]-phenoxy}-acetic acid 2(±)-{4-Chloro-2-[5-(3-fluoro-benzylcarbamoyl)-4,5,6,7-tetrahydro- 38.9thiazolo[5,4-c]pyridin-4-yl]-phenoxy}-acetic acid 3(±)-{4-Chloro-2-[5-(4-fluoro-benzylcarbamoyl)-4,5,6,7-tetrahydro- 124thiazolo[5,4-c]pyridin-4-yl]-phenoxy}-acetic acid 4(±)-[2-(5-Benzylcarbamoyl-4,5,6,7-tetrahydro-thiazolo[5,4- 62c]pyridin-4-yl)-4-chloro-phenoxy]-acetic acid 5{4-Chloro-2-[(R)-5-((1R,2R)-2-phenyl-cyclopropanecarbonyl}- 2.54,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4-yl]-phenoxy}-acetic acid 6{4-Chloro-2-[(R)-5-((1S,2S)-2-phenyl-cyclopropanecarbonyl}- 8714,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4-yl]-phenoxy}-acetic acid 7(4-Chloro-2-{(R)-5-[(1R,2R)-2-(3-fluoro-phenyl)- 2.8cyclopropanecarbonyl]-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4-yl}-phenoxy)-acetic acid 8(4-Chloro-2-{(R)-5-[(1R,2R)-2-(4-fluoro-phenyl)- 5cyclopropanecarbonyl]-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4-yl}-phenoxy)-acetic acid 9(4-Chloro-2-{(R)-5-[(1S,2S)-2-(4-fluoro-phenyl)- 462cyclopropanecarbonyl]-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4-yl}-phenoxy)-acetic acid 10{4-Chloro-2-[(R)-2-methyl-5-((1R,2R)-2-phenyl- 1.5cyclopropanecarbonyl)-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4-yl]-phenoxy}-acetic acid 11{4-Chloro-2-[(S)-2-methyl-5-((1R,2R)-2-phenyl- 570cyclopropanecarbonyl)-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4-yl]-phenoxy}-acetic acid 12(±)-4-(2-Carboxymethoxy-5-chloro-phenyl)-2-trifluoromethyl-6,7- 6.5dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic acid benzyl ester 13(±)-4-(2-Carboxymethoxy-5-chloro-phenyl)-2-isopropyl-6,7- 64.8dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic acid benzyl ester 14(±)-4-(2-Carboxymethoxy-5-chloro-phenyl)-2-cyclopropyl-6,7- 65.7dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic acid benzyl ester 15(±)-4-(2-Carboxymethoxy-5-chloro-phenyl)-2-methyl-6,7-dihydro- 6.24H-thiazolo[5,4-c]pyridine-5-carboxylic acid benzyl ester 16(±)-4-(2-Carboxymethoxy-5-chloro-phenyl)-2-ethyl-6,7-dihydro- 14.24H-thiazolo[5,4-c]pyridine-5-carboxylic acid benzyl ester 17(±)-2-Amino-4-(2-carboxymethoxy-5-chloro-phenyl)-6,7-dihydro- 2.24H-thiazolo[5,4-c]pyridine-5-carboxylic acid benzyl ester 18(S)-4-(2-Carboxymethoxy-5-chloro-phenyl)-2-methyl-6,7-dihydro- 6554H-thiazolo[5,4-c]pyridine-5-carboxylic acid benzyl ester 19(R)-4-(2-Carboxymethoxy-5-chloro-phenyl)-2-methyl-6,7-dihydro- 4.714H-thiazolo[5,4-c]pyridine-5-carboxylic acid benzyl ester 20(±)-2-Bromo-4-(2-carboxymethoxy-5-chloro-phenyl)-6,7-dihydro- 3.04H-thiazolo[5,4-c]pyridine-5-carboxylic acid benzyl ester 21(±)-(4-Chloro-2-{5-[3-(4-fluoro-phenoxy)-propionyl]-4,5,6,7- 19.6tetrahydro-thiazolo[5,4-c]pyridin-4-yl}-phenoxy)-acetic acid 22(±)-{4-Chloro-2-[trans-5-(2-phenyl-cyclopropanecarbonyl)- 3.94,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4-yl]-phenoxy}-acetic acid 23(±)-(4-Chloro-2-{trans-5-[2-(2-trifluoromethyl-phenyl)- 6.5cyclopropanecarbonyl]-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4-yl}-phenoxy)-acetic acid 24(±)-(4-Chloro-2-{trans-5-[2-(2-chloro-phenyl)- 7.3cyclopropanecarbonyl]-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4-yl}-phenoxy)-acetic acid 25(±)-{4-Chloro-2-[trans-5-(2-o-tolyl-cyclopropanecarbonyl)-4,5,6,7- 6.5tetrahydro-thiazolo[5,4-c]pyridin-4-yl]-phenoxy}-acetic acid 26(±)-(4-Chloro-2-{5-[3-(5-methoxy-1H-indol-3-yl)-propionyl]- 45.14,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4-yl}-phenoxy)-acetic acid 27(±)-(4-Chloro-2-{5-[3-(2-methyl-1H-indol-3-yl)-propionyl]-4,5,6,7- 219tetrahydro-thiazolo[5,4-c]pyridin-4-yl}-phenoxy)-acetic acid 28(±)-(4-Chloro-2-{5-[3-(1-methyl-1H-indol-3-yl)-propionyl]-4,5,6,7- 15.7tetrahydro-thiazolo[5,4-c]pyridin-4-yl}-phenoxy)-acetic acid 29(±)-{4-Chloro-2-[5-(3-o-tolyl-propionyl)-4,5,6,7-tetrahydro- 25.6thiazolo[5,4-c]pyridin-4-yl]-phenoxy}-acetic acid 30(±)-(4-Chloro-2-{5-[4-(2-fluoro-phenyl)-butyryl]-4,5,6,7-tetrahydro- 8.1thiazolo[5,4-c]pyridin-4-yl}-phenoxy)-acetic acid 31(±)-(4-Chloro-2-{5-[2-(2-chloro-benzyloxy)-acetyl]-4,5,6,7- 5.0tetrahydro-thiazolo[5,4-c]pyridin-4-yl}-phenoxy)-acetic acid 32(±)-(4-Chloro-2-{5-[2-(2,6-dimethyl-pyridin-3-yloxy)-acetyl]- 83.24,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4-yl}-phenoxy)-acetic acid 33(±)-{4-Chloro-2-[5-(3-indazol-1-yl-propionyl)-4,5,6,7-tetrahydro- 18.0thiazolo[5,4-c]pyridin-4-yl]-phenoxy}-acetic acid 34(±)-{4-Chloro-2-[5-(2-phenoxy-acetyl)-4,5,6,7-tetrahydro- 87.4thiazolo[5,4-c]pyridin-4-yl]-phenoxy}-acetic acid 35(±)-{4-Chloro-2-[5-((S)-3-phenyl-butyryl)-4,5,6,7-tetrahydro- 355thiazolo[5,4-c]pyridin-4-yl]-phenoxy}-acetic acid 36(±)-{4-Chloro-2-[5-(indane-2-carbonyl)-4,5,6,7-tetrahydro- 733thiazolo[5,4-c]pyridin-4-yl]-phenoxy}-acetic acid 37(±)-(4-Chloro-2-{5-[2-(1-phenyl-cyclopropyl)-acetyl]-4,5,6,7- 130tetrahydro-thiazolo[5,4-c]pyridin-4-yl}-phenoxy)-acetic acid 38(±)-{4-Chloro-2-[5-((R)-3-phenyl-butyryl)-4,5,6,7-tetrahydro- 12.2thiazolo[5,4-c]pyridin-4-yl]-phenoxy}-acetic acid 39(±)-{4-Chloro-2-[5-((±)-2-isochroman-1-yl-acetyl)-4,5,6,7- 99.1tetrahydro-thiazolo[5,4-c]pyridin-4-yl]-phenoxy}-acetic acid 40(±)-{4-Chloro-2-[5-(3,3-dimethyl-butyryl)-4,5,6,7-tetrahydro- 950thiazolo[5,4-c]pyridin-4-yl]-phenoxy}-acetic acid 41(±)-{4-Chloro-2-[5-(2-cyclopropyl-acetyl)-4,5,6,7-tetrahydro- 83.9thiazolo[5,4-c]pyridin-4-yl]-phenoxy}-acetic acid 42(±)-(4-Chloro-2-{5-[3-(3,5-dimethyl-isoxazol-4-yl)-propionyl]- 9454,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4-yl}-phenoxy)-acetic acid 43(±)-[4-Chloro-2-(5-cyclopropanecarbonyl-4,5,6,7-tetrahydro- 472thiazolo[5,4-c]pyridin-4-yl)-phenoxy]-acetic acid 44(±)-{4-Chloro-2-[5-(2-1H-indazol-3-yl-acetyl)-4,5,6,7-tetrahydro- 48.1thiazolo[5,4-c]pyridin-4-yl]-phenoxy}-acetic acid 45(±)-(4-Chloro-2-{5-[(E)-(3-phenyl-acryloyl)]-4,5,6,7-tetrahydro- 59.6thiazolo[5,4-c]pyridin-4-yl}-phenoxy)-acetic acid 46(±)-{4-Chloro-2-[5-(2-indan-2-yl-acetyl)-4,5,6,7-tetrahydro- 6.2thiazolo[5,4-c]pyridin-4-yl]-phenoxy}-acetic acid 47(±)-{4-Chloro-2-[(±)-5-(2,2-dimethyl-cyclopropanecarbonyl)- 37.14,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4-yl]-phenoxy}-acetic acid 48(±)-{4-Chloro-2-[5-(2-cyclohexyl-acetyl)-4,5,6,7-tetrahydro- 73thiazolo[5,4-c]pyridin-4-yl]-phenoxy}-acetic acid 49(±)-{4-Chloro-2-[5-(2-naphthalen-2-yl-acetyl)-4,5,6,7-tetrahydro- 15.8thiazolo[5,4-c]pyridin-4-yl]-phenoxy}-acetic acid 50(±)-{4-Chloro-2-[5-(2-naphthalen-1-yl-acetyl)-4,5,6,7-tetrahydro- 12.6thiazolo[5,4-c]pyridin-4-yl]-phenoxy}-acetic acid 51(±)-(4-Chloro-2-{5-[4-(4-fluoro-phenyl)-butyryl]-4,5,6,7-tetrahydro- 9.7thiazolo[5,4-c]pyridin-4-yl}-phenoxy)-acetic acid 52(±)-{4-Chloro-2-[5-(3-2,3-dihydro-indol-1-yl-propionyl)-4,5,6,7- 17.7tetrahydro-thiazolo[5,4-c]pyridin-4-yl]-phenoxy}-acetic acid 53(±)-{4-Chloro-2-[5-(3-3,4-dihydro-2H-quinolin-1-yl-propionyl)- 14.44,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4-yl]-phenoxy}-acetic acid 54(±)-(4-Chloro-2-{5-[(E)-3-(4-methoxy-phenyl)-acryloyl]-4,5,6,7- 41.2tetrahydro-thiazolo[5,4-c]pyridin-4-yl}-phenoxy)-acetic acid 55(±)-(4-Chloro-2-{5-[(E)-3-(4-fluoro-phenyl)-acryloyl]-4,5,6,7- 21.7tetrahydro-thiazolo[5,4-c]pyridin-4-yl}-phenoxy)-acetic acid 56(±)-{4-Chloro-2-[5-((E)-3-p-tolyl-acryloyl)-4,5,6,7-tetrahydro- 71.9thiazolo[5,4-c]pyridin-4-yl]-phenoxy}-acetic acid 57(±)-(4-Chloro-2-{5-[(E)-3-(2,4-difluoro-phenyl)-acryloyl]-4,5,6,7- 3.5tetrahydro-thiazolo[5,4-c]pyridin-4-yl}-phenoxy)-acetic acid 58(R)-4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H- 1.0thiazolo[5,4-c]pyridine-5-carboxylic acid 2,5-difluoro-benzyl ester 59(R)-4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H- 0.4thiazolo[5,4-c]pyridine-5-carboxylic acid 2,4-difluoro-benzyl ester 60(R)-4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H- 2.0thiazolo[5,4-c]pyridine-5-carboxylic acid 2,2-dimethyl-butyl ester 61(R)-4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H- 1.2thiazolo[5,4-c]pyridine-5-carboxylic acid 4-fluoro-benzyl ester 62(R)-4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H- 4.8thiazolo[5,4-c]pyridine-5-carboxylic acid 3-methoxy-3-methyl- butylester 63 (R)-4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H- 0.9thiazolo[5,4-c]pyridine-5-carboxylic acid 2,4-dimethyl-benzyl ester 64(R)-4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H- 0.3thiazolo[5,4-c]pyridine-5-carboxylic acid 2-chloro-5-fluoro-benzyl ester65 (R)-4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H- 1.3thiazolo[5,4-c]pyridine-5-carboxylic acid 3,3-dimethyl-butyl ester 66(R)-4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H- 0.7thiazolo[5,4-c]pyridine-5-carboxylic acid cyclohexylmethyl ester 67(R)-4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H- 0.4thiazolo[5,4-c]pyridine-5-carboxylic acid 3-methyl-butyl ester 68(R)-4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H- 0.5thiazolo[5,4-c]pyridine-5-carboxylic acid 5-chloro-2-fluoro-benzyl ester69 (R)-4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H- 4.2thiazolo[5,4-c]pyridine-5-carboxylic acid cyclobutylmethyl ester 70(R)-4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H- 2.8thiazolo[5,4-c]pyridine-5-carboxylic acid (±)-2-methyl-butyl ester 71(R)-4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H- 0.5thiazolo[5,4-c]pyridine-5-carboxylic acid 2,3-difluoro-benzyl ester 72(R)-4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H- 1.2thiazolo[5,4-c]pyridine-5-carboxylic acid 2,3-dimethyl-benzyl ester 73(R)-4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H- 0.3thiazolo[5,4-c]pyridine-5-carboxylic acid 2,6-difluoro-benzyl ester 74(R)-4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H- 1.4thiazolo[5,4-c]pyridine-5-carboxylic acid 3-fluoro-propyl ester 75(R)-4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H- 0.6thiazolo[5,4-c]pyridine-5-carboxylic acid 2-fluoro-benzyl ester 76(R)-4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H- 0.2thiazolo[5,4-c]pyridine-5-carboxylic acid 3-fluoro-benzyl ester 77(±)-4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H- 2.3thiazolo[5,4-c]pyridine-5-carboxylic acid 2-(3-fluoro-phenyl)-ethylester 78 (±)-4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H- 4.4thiazolo[5,4-c]pyridine-5-carboxylic acid 3-fluoro-benzyl ester 79(±)-4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H- 3.0thiazolo[5,4-c]pyridine-5-carboxylic acid 2-fluoro-benzyl ester 80(±)-4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H- 1.9thiazolo[5,4-c]pyridine-5-carboxylic acid 4-fluoro-benzyl ester 81(±)-4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H- 1.2thiazolo[5,4-c]pyridine-5-carboxylic acid 2,3-dichloro-benzyl ester 82(±)-4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H- 8.5thiazolo[5,4-c]pyridine-5-carboxylic acid 2,3-difluoro-benzyl ester 83(±)-4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H- 2.6thiazolo[5,4-c]pyridine-5-carboxylic acid 2,4-difluoro-benzyl ester 84(±)-4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H- 3.5thiazolo[5,4-c]pyridine-5-carboxylic acid 2-chloro-benzyl ester 85(±)-4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H- 7.0thiazolo[5,4-c]pyridine-5-carboxylic acid 3-chloro-benzyl ester 86(±)-4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H- 1.7thiazolo[5,4-c]pyridine-5-carboxylic acid 4-chloro-benzyl ester 87(±)-4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H- 8.7thiazolo[5,4-c]pyridine-5-carboxylic acid 2,6-dichloro-benzyl ester 88(±)-4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H- 6.4thiazolo[5,4-c]pyridine-5-carboxylic acid phenethyl ester 89(±)-4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H- 2.0thiazolo[5,4-c]pyridine-5-carboxylic acid 2,6-difluoro-benzyl ester 90(±)-4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H- 1.6thiazolo[5,4-c]pyridine-5-carboxylic acid indazol-1-ylmethyl ester 91(±)-4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H- 3.7thiazolo[5,4-c]pyridine-5-carboxylic acid 2-(2-ethyl-5-methyl-2H-pyrazol-3-yl)-ethyl ester 92(±)-4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H- 2.2thiazolo[5,4-c]pyridine-5-carboxylic acid 2-chloro-5-fluoro-benzyl ester93 (±)-4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H- 1.3thiazolo[5,4-c]pyridine-5-carboxylic acid 2,5-difluoro-benzyl ester 94(±)-4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H- 17.1thiazolo[5,4-c]pyridine-5-carboxylic acid 2,4-dichloro-benzyl ester 95(±)-4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H- 32.2thiazolo[5,4-c]pyridine-5-carboxylic acid pyrazin-2-ylmethyl ester 96(±)-4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H- 9.2thiazolo[5,4-c]pyridine-5-carboxylic acid cyclohexylmethyl ester 97(±)-4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H- 5.1thiazolo[5,4-c]pyridine-5-carboxylic acid benzooxazol-2-ylmethyl ester98 (±)-4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H- 17.8thiazolo[5,4-c]pyridine-5-carboxylic acid isobutyl ester 99(±)-4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H- 11.8thiazolo[5,4-c]pyridine-5-carboxylic acid butyl ester 100(±)-4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H- 7.1thiazolo[5,4-c]pyridine-5-carboxylic acid 2,4-dimethyl-benzyl ester 101(±)-4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H- 6.1thiazolo[5,4-c]pyridine-5-carboxylic acid 2,3-dimethyl-benzyl ester 102(±)-4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H- 8.3thiazolo[5,4-c]pyridine-5-carboxylic acid 5-chloro-2-fluoro-benzyl ester103 (R)-4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H- 2.3thiazolo[5,4-c]pyridine-5-carboxylic acid benzyl ester 104(S)-4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H- 286thiazolo[5,4-c]pyridine-5-carboxylic acid benzyl ester 105(±)-4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H- 3.5thiazolo[5,4-c]pyridine-5-carboxylic acid benzyl ester 106(±)-4-(2-Carboxymethoxy-5-cyano-phenyl)-6,7-dihydro-4H- 3.4thiazolo[5,4-c]pyridine-5-carboxylic acid benzyl ester 107(±)-[4-Chloro-2-(5-phenethylcarbamoyl-4,5,6,7-tetrahydro- 5.7thiazolo[5,4-c]pyridin-4-yl)-phenoxy]-acetic acid 108(±)-{4-Chloro-2-[5-(2-chloro-benzylcarbamoyl)-4,5,6,7-tetrahydro- 8.9thiazolo[5,4-c]pyridin-4-yl]-phenoxy}-acetic acid 109(±)-{4-Chloro-2-[5-(2-methoxy-benzylcarbamoyl)-4,5,6,7- 5.5tetrahydro-thiazolo[5,4-c]pyridin-4-yl]-phenoxy}-acetic acid 110(±)-{4-Chloro-2-[5-(2-methoxy-benzylthiocarbamoyl)-4,5,6,7- 9.5tetrahydro-thiazolo[5,4-c]pyridin-4-yl]-phenoxy}-acetic acid 111(±)-4-(2-Carboxymethoxy-5-chloro-phenyl)-2-propyl-6,7-dihydro- 86.44H-thiazolo[5,4-c]pyridine-5-carboxylic acid benzyl ester 112(±)-4-(2-Carboxymethoxy-5-chloro-phenyl)-2-phenyl-6,7-dihydro- 30.94H-thiazolo[5,4-c]pyridine-5-carboxylic acid benzyl ester 113(±)-4-(2-Carboxymethoxy-5-chloro-phenyl)-2- 254methanesulfonylamino-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic acid benzyl ester 114(±)-4-(2-Carboxymethoxy-5-chloro-phenyl)-2- 678cyclopropanesulfonylamino-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic acid benzyl ester 115(±)-4-(2-Carboxymethoxy-5-chloro-phenyl)-2- 491(cyclopropanecarbonyl-amino)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic acid benzyl ester 116(±)-2-Acetylamino-4-(2-carboxymethoxy-5-chloro-phenyl)-6,7- 857dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic acid benzyl ester 117(±)-4-(2-Carboxymethoxy-5-chloro-phenyl)-2-dimethylamino-6,7- 204dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic acid benzyl ester 118(±)-4-(2-Carboxymethoxy-5-fluoro-phenyl)-6,7-dihydro-4H- 8.3thiazolo[5,4-c]pyridine-5-carboxylic acid benzyl ester 119(±)-4-[2-((R)-1-Carboxy-ethoxy)-5-chloro-phenyl]-6,7-dihydro-4H- 18.5thiazolo[5,4-c]pyridine-5-carboxylic acid benzyl ester 120(±)-4-[2-((S)-1-Carboxy-ethoxy)-5-chloro-phenyl]-6,7-dihydro-4H- 64.4thiazolo[5,4-c]pyridine-5-carboxylic acid benzyl ester

Radioligand Displacement Assay-Human Serum Albumin (HSA):

Radioligand displacement assay in presence of human serum albumin (HSA)was performed as described above, with following modifications.Binding-Buffer-HSA: Binding-buffer+0.5% Sigma Albumin from Human serumA1887 (instead of 0.1% BSA). A volume of 25 μl test compound, previouslydiluted in Binding-Buffer-HSA was placed into each well. After additionof 75 μl Binding-Buffer-HSA, 50 μl of ³H-PGD₂ (at 2.5 nM (220.000dpm/well) from ANAWA ART0662) was added to each well. Remaining protocolwas identical as described above.

Eosinophil Shape Change Assay with Human Plasma

After obtaining informed consent, blood samples were drawn byvenipuncture according to the protocol approved by the ethics committeeof Basel, Switzerland. Polymorphonuclear leukocytes (containingeosinophils, basophils and neutrophils) were isolated using thePolymorphprep™ method (Axis-Shield). In brief, anticoagulated wholeblood was layered onto a Polymorphprep gradient (density 1.113 g/ml) andcentrifuged at 500 g for 30 min. The polymorphonuclear cell fraction washarvested and depleted for erythrocytes by hypotonic saline lysis.

The polymorphonuclear cells were resuspended in assay buffer (1×PBS withCa²⁺/Mg²⁺ supplemented with 0.1% BSA, 10 mM HEPES, and 10 mM Glucose, pH7.4) at 5×10⁶ cells/ml and stained with anti-CD49d-APC((APC=Allophycocyanin) for 1 hour at RT. Test compounds, at variousconcentrations, were preincubated 10 min in human plasma (anticoagulatedwith a thrombin inhibitor). Then, human plasma was added to thepolymorphonuclear cells to 50% of final assay volume withpolymorphonuclear cells at 4×10⁶ cells/ml. After incubation for 10minutes at 37° C., the polymorphonuclear cells were activated for 5 minat 37° C. by addition of PGD₂ at 100 nM final concentration. Activationwas stopped by addition of 0.5 ml paraformaldehyde (1%).

Immediately after fixation with paraformaldehyde, the samples wereanalyzed by FACSCanto flow cytometer (BD Biosciences) and target cellswere identified by their forward-scatter (FSC) and side-scatter (SSC)characteristics. Eosinophils were identified by the anti-CD49d-APCsignal and their characteristic side-scatter (SSC) profile. Shape changeresponses, indicative of eosinophil activation, were quantified as thepercent of cells with an increased forward-scatter.

Intracellular Calcium Mobilization Assay (FLIPR):

Cells (HEK-293), stably expressing the hCRTH2 receptor under the controlof the cytomegalovirus promotor from a single insertion of theexpression vector pcDNA5 (Invitrogen), are grown to confluency in DMEM(low glucose, Gibco) medium supplemented with 10% fetal calf serum(Bioconcept, Switzerland) under standard mammalian cell cultureconditions (37° C. in a humidified atmosphere of 5% CO₂). Cells aredetached from culture dishes using a dissociation buffer (0.02% EDTA inPBS, Gibco) for 1 min, and collected by centrifugation at 200 g at rtfor 5 min in assay buffer (equal parts of Hank's BSS (HBSS, Bioconcept)and DMEM (low glucose, without phenol red, Gibco)). After incubation for45 min (37° C. and 5% CO₂) in the presence of 1 μM Fluo-4 and 0.04%Pluronic F-127 (both Molecular Probes), and 20 mM HEPES (Gibco) in assaybuffer, the cells are washed with and resuspended in assay buffer, thenseeded onto 384-well FLIPR assay plates (Greiner) at 50,000 cells in 66μl per well, and sedimented by centrifugation.

Stock solutions of test compounds are made up at a concentration of 10mM in DMSO, and serially diluted in assay buffer to concentrationsrequired for inhibition dose response curves. Prostaglandin D₂ (Biomol,Plymouth Meeting, Pa.) is used as an agonist.

A FLIPR Tetra instrument (Molecular Devices) is operated according tothe manufacturers standard instructions, adding 4 μl of test compounddissolved at 10 mM in DMSO and diluted prior to the experiment in assaybuffer to obtain the desired final concentration. 10 μl of 80 nMprostaglandin D₂ (Biomol, Plymouth Meeting, Pa.) in assay buffer,supplemented with 0.8% bovine serum albumin (fatty acid content <0.02%,Sigma), is then added to obtain a final concentration of 10 nM and 0.1%,respectively. Changes in fluorescence are monitored before and after theaddition of test compounds at λ_(ex)=488 nm and λ_(em)=540 nm. Emissionpeak values above base level after prostaglandin D₂ addition areexported after base line subtraction. Values are normalized tohigh-level control (no test compound added) after subtraction of baseline value (no prostaglandin D₂ added). The program XLIfit 3.0 (IDBS) isused to fit the data to a single site dose response curve of theequation (A+((B−A)/(1+((C/x)̂D)))) and to calculate the IC₅₀ values.

1. A compound of formula (I):

wherein Y represents —NH—, —O— or a bond; Z represents O or S; R¹represents (C₃-C₆)alkyl which is unsubstituted, mono-substituted with(C₁-C₄)alkoxy, or mono-, di- or tri-substituted with fluoro;(C₁-C₄)alkyl which is mono-substituted with (C₄-C₆)cycloalkyl,optionally substituted cyclopropyl, optionally substituted aryl,optionally substituted heteroaryl, optionally substituted heterocyclyl,optionally substituted aryloxy, optionally substituted heteroaryloxy, oroptionally substituted aryl-(C₁-C₂)alkoxy; (C₂-C₄)alkenyl which ismono-substituted with optionally substituted aryl; or (C₃-C₆)cycloalkylwhich is unsubstituted, mono-substituted with optionally substitutedaryl or mono- or di-substituted with (C₁-C₄)alkyl; R² represents halogenor cyano; R³ represents hydrogen or methyl; R⁴ represents hydrogen,(C₁-C₄)alkyl, (C₃-C₆)cycloalkyl, halogen, phenyl, (C₁-C₂)fluoroalkyl, or—NR⁵R⁶; R⁵ represents hydrogen or methyl; and R⁶ represents hydrogen,(C₁-C₄)alkyl, (C₁-C₄)alkyl-carbonyl, (C₁-C₄)alkyl-sulfonyl,(C₃-C₆)cycloalkyl-carbonyl, or (C₃-C₆)cycloalkyl-sulfonyl; or a saltthereof.
 2. The compound according to claim 1, wherein Y represents —O—or a bond; Z represents O; R¹ represents (C₃-C₆)alkyl which isunsubstituted, mono-substituted with (C₁-C₄)alkoxy, or mono-substitutedwith fluoro; (C₁-C₄)alkyl which is mono-substituted with(C₄-C₆)cycloalkyl, optionally substituted aryl, optionally substitutedheteroaryl, or optionally substituted aryl-(C₁-C₂)alkoxy; (C₂-C₄)alkenylwhich is mono-substituted with optionally substituted aryl; or(C₃-C₆)cycloalkyl which is mono-substituted with optionally substitutedaryl; R² represents halogen or cyano; R³ represents hydrogen; and R⁴represents hydrogen, methyl, bromo, trifluoromethyl, or —NH₂; or a saltthereof.
 3. The compound according to claim 1, wherein Y represents —O—;Z represents O; R¹ represents (C₃-C₆)alkyl which is unsubstituted,mono-substituted with (C₁-C₄)alkoxy, or mono-, di- or tri-substitutedwith fluoro; or (C₁-C₄)alkyl which is mono-substituted with(C₄-C₆)cycloalkyl, optionally substituted aryl, or optionallysubstituted heteroaryl; R² represents halogen or cyano; R³ representshydrogen or methyl; R⁴ represents hydrogen, (C₁-C₄)alkyl,(C₃-C₆)cycloalkyl, halogen, phenyl, (C₁-C₂)fluoroalkyl, or —NR⁵R⁶; R⁵represents hydrogen or methyl; and R⁶ represents hydrogen, (C₁-C₄)alkyl,(C₁-C₄)alkyl-carbonyl, (C₁-C₄)alkyl-sulfonyl,(C₃-C₆)cycloalkyl-carbonyl, or (C₃-C₆)cycloalkyl-sulfonyl; or a saltthereof.
 4. The compound according to claim 1, wherein Y represents —O—;or a salt thereof.
 5. The compound according to claim 1, wherein Yrepresents a bond; or a salt thereof.
 6. The compound according to claim1, wherein Z represents O; or a salt thereof.
 7. The compound accordingto claim 1, wherein R¹ represents (C₁-C₄)alkyl which is mono-substitutedwith (C₄-C₆)cycloalkyl, optionally substituted aryl, or optionallysubstituted aryl-(C₁-C₂)alkoxy; (C₂-C₄)alkenyl which is mono-substitutedwith optionally substituted aryl; or (C₃-C₆)cycloalkyl which ismono-substituted with optionally substituted aryl; or a salt thereof. 8.The compound according to claim 1, wherein R¹ represents (C₃-C₆)alkylwhich is unsubstituted, mono-substituted with (C₁-C₄)alkoxy, ormono-substituted with fluoro; or (C₁-C₄)alkyl which is mono-substitutedwith (C₄-C₆)cycloalkyl, optionally substituted aryl, or optionallysubstituted heteroaryl; or a salt thereof.
 9. The compound according toclaim 1, wherein R³ represents hydrogen; or a salt thereof.
 10. Thecompound according to claim 1, wherein R⁴ represents hydrogen,(C₁-C₄)alkyl, halogen, trifluoromethyl, or —NH₂; or a salt thereof. 11.A The compound according to claim 1, wherein the compound is:{4-Chloro-2-[5-(2-fluoro-benzylcarbamoyl)-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4-yl]-phenoxy}-aceticacid;{4-Chloro-2-[5-(3-fluoro-benzylcarbamoyl)-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4-yl]-phenoxy}-aceticacid;{4-Chloro-2-[5-(4-fluoro-benzylcarbamoyl)-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4-yl]-phenoxy}-aceticacid;[2-(5-Benzylcarbamoyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4-yl)-4-chloro-phenoxy]-aceticacid;{4-Chloro-2-[(R)-5-((1R,2R)-2-phenyl-cyclopropanecarbonyl)-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4-yl]-phenoxy}-aceticacid;{4-Chloro-2-[(R)-5-((1S,2S)-2-phenyl-cyclopropanecarbonyl)-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4-yl]-phenoxy}-aceticacid;(4-Chloro-2-{(R)-5-[(1R,2R)-2-(3-fluoro-phenyl)-cyclopropanecarbonyl]-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4-yl}-phenoxy)-aceticacid;(4-Chloro-2-{(R)-5-[(1R,2R)-2-(4-fluoro-phenyl)-cyclopropanecarbonyl]-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4-yl}-phenoxy)-aceticacid;(4-Chloro-2-{(R)-5-[(1S,2S)-2-(4-fluoro-phenyl)-cyclopropanecarbonyl]-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4-yl}-phenoxy)-aceticacid;{4-Chloro-2-[(R)-2-methyl-5-((1R,2R)-2-phenyl-cyclopropanecarbonyl)-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4-yl]-phenoxy}-aceticacid;{4-Chloro-2-[(S)-2-methyl-5-((1R,2R)-2-phenyl-cyclopropanecarbonyl)-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4-yl]-phenoxy}-aceticacid;4-(2-Carboxymethoxy-5-chloro-phenyl)-2-trifluoromethyl-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylicacid benzyl ester;4-(2-Carboxymethoxy-5-chloro-phenyl)-2-isopropyl-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylicacid benzyl ester;4-(2-Carboxymethoxy-5-chloro-phenyl)-2-cyclopropyl-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylicacid benzyl ester;4-(2-Carboxymethoxy-5-chloro-phenyl)-2-methyl-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylicacid benzyl ester;4-(2-Carboxymethoxy-5-chloro-phenyl)-2-ethyl-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylicacid benzyl ester;2-Amino-4-(2-carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylicacid benzyl ester;(S)-4-(2-Carboxymethoxy-5-chloro-phenyl)-2-methyl-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylicacid benzyl ester;(R)-4-(2-Carboxymethoxy-5-chloro-phenyl)-2-methyl-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylicacid benzyl ester;2-Bromo-4-(2-carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylicacid benzyl ester;(4-Chloro-2-{5-[3-(4-fluoro-phenoxy)-propionyl]-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4-yl}-phenoxy)-aceticacid;{4-Chloro-2-[trans-5-(2-phenyl-cyclopropanecarbonyl)-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4-yl]-phenoxy}-aceticacid;(4-Chloro-2-{trans-5-[2-(2-trifluoromethyl-phenyl)-cyclopropanecarbonyl]-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4-yl}-phenoxy)-aceticacid;(4-Chloro-2-{trans-5-[2-(2-chloro-phenyl)-cyclopropanecarbonyl]-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4-yl}-phenoxy)-aceticacid;{4-Chloro-2-[trans-5-(2-o-tolyl-cyclopropanecarbonyl)-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4-yl]-phenoxy}-aceticacid;(4-Chloro-2-{5-[3-(5-methoxy-1H-indol-3-yl)-propionyl]-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4-yl}-phenoxy)-aceticacid;(4-Chloro-2-{5-[3-(2-methyl-1H-indol-3-yl)-propionyl]-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4-yl}-phenoxy)-aceticacid;(4-Chloro-2-{5-[3-(1-methyl-1H-indol-3-yl)-propionyl]-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4-yl}-phenoxy)-aceticacid;{4-Chloro-2-[5-(3-o-tolyl-propionyl)-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4-yl]-phenoxy}-aceticacid;(4-Chloro-2-{5-[4-(2-fluoro-phenyl)-butyryl]-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4-yl}-phenoxy)-aceticacid;(4-Chloro-2-{5-[2-(2-chloro-benzyloxy)-acetyl]-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4-yl}-phenoxy)-aceticacid;(4-Chloro-2-{5-[2-(2,6-dimethyl-pyridin-3-yloxy)-acetyl]-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4-yl}-phenoxy)-aceticacid;{4-Chloro-2-[5-(3-indazol-1-yl-propionyl)-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4-yl]-phenoxy}-aceticacid;{4-Chloro-2-[5-(2-phenoxy-acetyl)-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4-yl]-phenoxy}-aceticacid;{4-Chloro-2-[5-((S)-3-phenyl-butyryl)-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4-yl]-phenoxy}-aceticacid;{4-Chloro-2-[5-(indane-2-carbonyl)-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4-yl]-phenoxy}-aceticacid;(4-Chloro-2-{5-[2-(1-phenyl-cyclopropyl)-acetyl]-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4-yl}-phenoxy)-aceticacid;{4-Chloro-2-[5-((R)-3-phenyl-butyryl)-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4-yl]-phenoxy}-aceticacid;{4-Chloro-2-[5-(2-isochroman-1-yl-acetyl)-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4-yl]-phenoxy}-aceticacid;{4-Chloro-2-[5-(3,3-dimethyl-butyryl)-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4-yl]-phenoxy}-aceticacid;{4-Chloro-2-[5-(2-cyclopropyl-acetyl)-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4-yl]-phenoxy}-aceticacid;(4-Chloro-2-{5-[3-(3,5-dimethyl-isoxazol-4-yl)-propionyl]-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4-yl}-phenoxy)-aceticacid;[4-Chloro-2-(5-cyclopropanecarbonyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4-yl)-phenoxy]-aceticacid;{4-Chloro-2-[5-(2-1H-indazol-3-yl-acetyl)-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4-yl]-phenoxy}-aceticacid;(4-Chloro-2-{5-[(E)-(3-phenyl-acryloyl)]-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4-yl}-phenoxy)-aceticacid;{4-Chloro-2-[5-(2-indan-2-yl-acetyl)-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4-yl]-phenoxy}-aceticacid;{4-Chloro-2-[5-(2,2-dimethyl-cyclopropanecarbonyl)-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4-yl]-phenoxy}-aceticacid;{4-Chloro-2-[5-(2-cyclohexyl-acetyl)-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4-yl]-phenoxy}-aceticacid;{4-Chloro-2-[5-(2-naphthalen-2-yl-acetyl)-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4-yl]-phenoxy}-aceticacid;{4-Chloro-2-[5-(2-naphthalen-1-yl-acetyl)-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4-yl]-phenoxy}-aceticacid;(4-Chloro-2-{5-[4-(4-fluoro-phenyl)-butyryl]-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4-yl}-phenoxy)-aceticacid;{4-Chloro-2-[5-(3-2,3-dihydro-indol-1-yl-propionyl)-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4-yl]-phenoxy}-aceticacid;{4-Chloro-2-[5-(3-3,4-dihydro-2H-quinolin-1-yl-propionyl)-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4-yl]-phenoxy}-aceticacid;(4-Chloro-2-{5-[(E)-3-(4-methoxy-phenyl)-acryloyl]-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4-yl}-phenoxy)-aceticacid;(4-Chloro-2-{5-[(E)-3-(4-fluoro-phenyl)-acryloyl]-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4-yl}-phenoxy)-aceticacid;{4-Chloro-2-[5-((E)-3-p-tolyl-acryloyl)-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4-yl]-phenoxy}-aceticacid;(4-Chloro-2-{5-[(E)-3-(2,4-difluoro-phenyl)-acryloyl]-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4-yl}-phenoxy)-aceticacid;(R)-4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylicacid 2,5-difluoro-benzyl ester;(R)-4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylicacid 2,4-difluoro-benzyl ester;(R)-4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylicacid 2,2-dimethyl-butyl ester;(R)-4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylicacid 4-fluoro-benzyl ester;(R)-4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylicacid 3-methoxy-3-methyl-butyl ester;(R)-4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylicacid 2,4-dimethyl-benzyl ester;(R)-4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylicacid 2-chloro-5-fluoro-benzyl ester;(R)-4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylicacid 3,3-dimethyl-butyl ester;(R)-4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylicacid cyclohexylmethyl ester;(R)-4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylicacid 3-methyl-butyl ester;(R)-4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylicacid 5-chloro-2-fluoro-benzyl ester;(R)-4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylicacid cyclobutylmethyl ester;(R)-4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylicacid 2-methyl-butyl ester;(R)-4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylicacid 2,3-difluoro-benzyl ester;(R)-4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylicacid 2,3-dimethyl-benzyl ester;(R)-4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylicacid 2,6-difluoro-benzyl ester;(R)-4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylicacid 3-fluoro-propyl ester;(R)-4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylicacid 2-fluoro-benzyl ester;(R)-4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylicacid 3-fluoro-benzyl ester;4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylicacid 2-(3-fluoro-phenyl)-ethyl ester;4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylicacid 3-fluoro-benzyl ester;4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylicacid 2-fluoro-benzyl ester;4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylicacid 4-fluoro-benzyl ester;4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylicacid 2,3-dichloro-benzyl ester;4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylicacid 2,3-difluoro-benzyl ester;4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylicacid 2,4-difluoro-benzyl ester;4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylicacid 2-chloro-benzyl ester;4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylicacid 3-chloro-benzyl ester;4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylicacid 4-chloro-benzyl ester;4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylicacid 2,6-dichloro-benzyl ester;4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylicacid phenethyl ester;4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylicacid 2,6-difluoro-benzyl ester;4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylicacid indazol-1-ylmethyl ester;4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylicacid 2-(2-ethyl-5-methyl-2H-pyrazol-3-yl)-ethyl ester;4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylicacid 2-chloro-5-fluoro-benzyl ester;4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylicacid 2,5-difluoro-benzyl ester;4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylicacid 2,4-dichloro-benzyl ester;4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylicacid pyrazin-2-ylmethyl ester;4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylicacid cyclohexylmethyl ester;4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylicacid benzooxazol-2-ylmethyl ester;4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylicacid isobutyl ester;4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylicacid butyl ester;4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylicacid 2,4-dimethyl-benzyl ester;4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylicacid 2,3-dimethyl-benzyl ester;4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylicacid 5-chloro-2-fluoro-benzyl ester;(R)-4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylicacid benzyl ester;(S)-4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylicacid benzyl ester;4-(2-Carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylicacid benzyl ester;4-(2-Carboxymethoxy-5-cyano-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylicacid benzyl ester;[4-Chloro-2-(5-phenethylcarbamoyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4-yl)-phenoxy]-aceticacid;{4-Chloro-2-[5-(2-chloro-benzylcarbamoyl)-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4-yl]-phenoxy}-aceticacid;{4-Chloro-2-[5-(2-methoxy-benzylcarbamoyl)-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4-yl]-phenoxy}-aceticacid;{4-Chloro-2-[5-(2-methoxy-benzylthiocarbamoyl)-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-4-yl]-phenoxy}-aceticacid;4-(2-Carboxymethoxy-5-chloro-phenyl)-2-propyl-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylicacid benzyl ester;4-(2-Carboxymethoxy-5-chloro-phenyl)-2-phenyl-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylicacid benzyl ester;4-(2-Carboxymethoxy-5-chloro-phenyl)-2-methanesulfonylamino-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylicacid benzyl ester;4-(2-Carboxymethoxy-5-chloro-phenyl)-2-cyclopropanesulfonylamino-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylicacid benzyl ester;4-(2-Carboxymethoxy-5-chloro-phenyl)-2-(cyclopropanecarbonyl-amino)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylicacid benzyl ester;2-Acetylamino-4-(2-carboxymethoxy-5-chloro-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylicacid benzyl ester;4-(2-Carboxymethoxy-5-chloro-phenyl)-2-dimethylamino-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylicacid benzyl ester;4-(2-Carboxymethoxy-5-fluoro-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylicacid benzyl ester;4-[2-((R)-1-Carboxy-ethoxy)-5-chloro-phenyl]-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylicacid benzyl ester; or4-[2-((S)-1-Carboxy-ethoxy)-5-chloro-phenyl]-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylicacid benzyl ester; or a salt thereof.
 12. A pharmaceutical compositioncomprising a compound according to claim 1, or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable carrier. 13.(canceled)
 14. A method of treating or preventing a disease comprisingadministering to a subject in need thereof a therapeutically effectiveamount of the compound according to claim 1, wherein the disease is achronic and acute allergic or immune disease or disorder; aneosinophil-related disease or basophil-related diseases.
 15. The methodaccording to claim 14, wherein the chronic and acute allergic or immunedisease or disorder is asthma, allergic asthma, eosinophilic asthma,severe asthma, rhinitis, allergic rhinitis, angioedema, insect venomallergy, drug allergies, allergic sinusitis, allergic nephritis,allergic conjunctivitis, atopic dermatitis, bronchial asthma, foodallergy, systemic mast cell disorders, anaphylactic shock, urticaria,eczema, ulcerative colitis, chronic obstructive pulmonary disease(COPD), inflammatory bowel disease and rheumatoid arthritis.
 16. Themethod according to claim 14, wherein the eosinophil-related disease isa small vessel vasculitide or a hypereosinophilic syndrome.
 17. Themethod according to claim 16, wherein the small vessel vasculitide isChurg-Stauss syndrome Wegener's granulomatosis, microscopic polyangiitisor organ-specific subsets of the latter.
 18. The method according toclaim 16, wherein the hypereosinophilic syndrome is eosinophilicpneumonia, eosinophilic esophagitis, reflux esophagitis, eosinohilicendocarditis (Loeffler's endocarditis), eosinophilia-myalgia syndrome,eosinophilic fasciitis, eosinohilic pustular folliculitis (Ofuji'sdisease), eosinophilic ulcers, angiolymphoid hyperplasia witheosinophilia (ALHE), eosinophilic cellulitis (Wells syndrome), chroniceosinophilic leukemia and DRESS syndrome (Drug Rash with Eosinophiliaand Systemic Symptoms).
 19. The method according to claim 14, whereinthe basophil-related disease is basophilic leukemia or basophilicleukocytosis.